Physiology, ecology and industrial applications of aroma formation in yeast

Maria C Dzialo; Rahel Park; Jan Steensels; Bart Lievens; Kevin J Verstrepen

doi:10.1093/femsre/fux031

Physiology, ecology and industrial applications of aroma formation in yeast

Dzialo, Maria C; Park, Rahel; Steensels, Jan; Lievens, Bart; Verstrepen, Kevin J 2017-08-01 00:00:00 Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 FEMS Microbiology Reviews, fux031, 41, 2017, S95–S128 doi: 10.1093/femsre/fux031 Review Article REVIEW ARTICLE Physiology, ecology and industrial applications of aroma formation in yeast 1,2 1,2 1,2 3 Maria C. Dzialo , Rahel Park , Jan Steensels , Bart Lievens 1,2,∗ and Kevin J. Verstrepen Laboratory for Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Gaston Geenslaan 1, B-3001 Leuven, Belgium, Laboratory for Systems Biology, VIB Center for Microbiology, Bio-Incubator, Gaston Geenslaan 1, 3001 Leuven, Belgium and Laboratory for Process Microbial Ecology and Bioinspirational Management (PME&BIM), Department of Microbial and Molecular Systems, KU Leuven, Campus De Nayer, Fortsesteenweg 30A B-2860 Sint-Katelijne Waver, Belgium Corresponding author: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, VIB Center for Microbiology, Bio-Incubator, Gaston Geenslaan 1, B-3001 Leuven, Belgium. Tel: +32 (0)16 75 1390; E-mail: kevin.verstrepen@kuleuven.vib.be One sentence summary: This review explores the biochemical pathways leading to production of a wide array of aroma compounds, the various industrial applications that have been developed around use of aroma compounds, as well as the newly uncovered physiological and ecological roles the various compounds may play. Editor: Eddy Smid ABSTRACT Yeast cells are often employed in industrial fermentation processes for their ability to efficiently convert relatively high concentrations of sugars into ethanol and carbon dioxide. Additionally, fermenting yeast cells produce a wide range of other compounds, including various higher alcohols, carbonyl compounds, phenolic compounds, fatty acid derivatives and sulfur compounds. Interestingly, many of these secondary metabolites are volatile and have pungent aromas that are often vital for product quality. In this review, we summarize the different biochemical pathways underlying aroma production in yeast as well as the relevance of these compounds for industrial applications and the factors that influence their production during fermentation. Additionally, we discuss the different physiological and ecological roles of aroma-active metabolites, including recent findings that point at their role as signaling molecules and attractants for insect vectors. INTRODUCTION 1996), and capping off with an in-depth look at the phenotypic and genetic diversity of nearly 200 industrial yeasts last year, When presented with the appropriate nutrients, yeasts pro- including a detailed profiling of differences in aroma formation duce complex bouquets of aroma compounds including esters, (Gallone et al. 2016; Gonc¸alves et al. 2016). Interestingly, these re- higher alcohols, carbonyls, fatty acid derivatives and sulfur com- cent studies demonstrate that humans have helped drive the pounds. Moreover, while not directly synthesized by yeasts, domestication of yeasts, at least partly based on their ability to volatile thiols and monoterpenes are sometimes released from selectively produce desired aromas and reduce unwanted com- odorless precursors by yeast-derived enzymes (Tominaga et al. pounds. 1998;Moreira et al. 2005). Our understanding of the fermenta- Given its importance in product quality, much effort has been tion process and the associated aroma production by yeast has devoted to fine-tune flavor production by yeast in an indus- increased exponentially over the last centuries, from the discov- trial setting. Globally, two approaches can be applied to steer ery of yeast cells in 1680, to the sequencing of the entire Saccha- the yeast’s physiology to alter aroma production: adjusting the romyces cerevisiae genome just two decades ago (Goffeau et al. Received: 17 February 2017; Accepted: 6 June 2017 FEMS 2017. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. S95 Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S96 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 1. Overview of aroma compound production. This review covers a large array of aroma compounds produced during yeast fermentation. The basic fermentation of pyruvate (green/red) leads to several carbon-based compounds, including ethanol and carbon dioxide. Pyruvate also feeds into the anabolism of amino acids, leading to production of vicinal diketones (pink). Metabolism of amino acids is responsible for numerous aroma compounds including higher alcohols and esters (purple) as well as sulfur-containing compounds (blue). Additionally, the phenolic compounds are derived from molecules found in the media (orange). Compoundsshown in darker shades are considered intermediates while lighter shades are aroma compounds discussed in this review. Dotted lines indicate import/export of compounds, solid lines represent biochemical reactions (not indicative of number of reactions). fermentation environment or modifying the genotype of the In this review, we provide an overview of the current under- production strain. Adjusting the environmental parameters standing of aroma production in yeasts in an industrial, phys- can be a convenient, often very powerful, way to optimize iological and ecological context. We attempt to provide a more production without complex biotechnological procedures nor global review covering major compounds discussed commonly a thorough understanding of basic yeast physiology. How- in industry and ecology (Fig. 1). For each metabolite category, ever, given the recent expansion of the available yeast bio- we first illustrate the biochemical pathways which are crucial diversity, strategies to modify yeasts and the genetic toolbox for understanding the rationale behind much of the industrial to genetically engineer strains, biotechnologists can now se- research. Note that much of the biochemical review in this pa- lect or develop new yeasts with aromatic properties far be- per will refer to Saccharomyces cerevisiae since research into the yond what is achievable through adjustment of environmental specific mechanisms of the fermentation process is commonly parameters. based on this species, given its central role as a model organism While humans have been advancing, and refining the ex- and as a robust fermenter in industry. We then discuss the in- ploitation of yeast aroma for several millennia, it remained un- dustrial roles of the aroma compounds that humans have devel- known why yeast cells produce these flavor-active molecules oped. We also highlight key environmental parameters, such as in the first place. Over the past decades, several hypotheses temperature and medium composition, that are commonly ad- for possible physiological roles have been proposed, includ- justed to affect specific compound production as well as some ing synthesis of specific cellular building blocks, redox balanc- modifications to genetic background that have been developed ing and detoxification reactions, but the evidence for these re- to influence aroma production. Lastly, we explore some of the mained very limited. Recent studies, however, have begun to possible physiological and ecological roles of these aroma com- uncover a fundamental and central role of aroma production pounds. in the lifestyle of yeast. Specifically, it has been shown that yeast-derived volatiles can have integral roles in natural envi- ronments, ranging from signaling information to animal vec- PRIMARY FERMENTATION METABOLITES: tors, regulation of fungal growth and communication between ETHANOL yeast cells or colonies (Richard et al. 1996; Bruce et al. 2005; In many industrial fermentation processes, ethanol is the most Leroy et al. 2011;Davis et al. 2013). The interaction between important compound produced by yeast. Moreover, it is the pro- yeasts and insects has been studied intensively the past decade duction of this primary metabolite that originally sparked inter- and there is increasing evidence that attraction of many in- est for the fermentation of beverages. Early civilizations devel- sect species to fermenting fruits is mediated by the volatiles oped fermentation methods to exploit the benefits of ethanol; emitted by the yeasts rather than by the fruit itself (Becher ethanol prolongs shelf-life, improves digestibility and acts as et al. 2012). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S97 Figure 2. Production of ethanol, acetaldehyde, acetic acid, and CO . Fermentable carbons are assimilated from the medium and converted to glycerol or pyruvate via glycolysis. Pyruvate can be shuttled towards the TCA cycle and respiration (left) or towards alcoholic fermentation (right). For some conversions, multiple enzymes can perform the reaction and are indicated on the figure. Note: Ald4, Ald5 and Adh3 are mitochondrial enzymes but perform the same reactions as the other cytosolic ALD and ADH enzymes. a euphoriant (Alba-Lois and Segal-Kischinevzky 2010). Today, fermentation and respiration. In direct competition with pyru- ethanol still forms the basis of many fermented products, ei- vate dehydrogenase, PDCs can remove excess pyruvate from the ther destined for consumption or for renewable energy. More- pathway and divert it towards ethanol production. over, ethanol is a volatile aroma compound, although its sen- Acetaldehyde is subsequently converted into ethanol by an sorial properties are perhaps less pronounced than some of the alcohol dehydrogenase (ADH). This type of oxidoreductase can more flavorful molecules that are also formed as byproducts of catalyze the reversible interconversion of alcohols and the cor- the fermentation pathway. responding aldehydes or ketones. The wide array of substrates available for ADHs throughout the metabolic pathways requires substantial regulation to ensure a balance of the desired prod- Biochemistry of ethanol production ucts and intermediates. It is therefore not surprising that eu- karyotes, even humans, have numerous ADH enzymes. Even a Although yeasts have been utilized for their fermentative capac- simple eukaryote like S. cerevisiae has seven ADH genes as well ity for millennia, the molecular components of this basic path- as several aryl-alcohol dehydrogenases (AAD). Adh1 is the pri- way were only discovered in the last few decades (Bennetzen mary enzyme for producing ethanol during fermentation and for and Hall 1982; Schmitt, Ciriacy and Zimmermann 1983). + replenishing the pool of NAD , while Adh2 is glucose repress- Central metabolism begins with the basic conversion of sug- ible and will oxidize ethanol as a carbon source when needed ars into pyruvate, yielding energy in the form of ATP and reduced (Leskovac, Trivic´ and Pericin 2002). Adh3 is constitutively ex- NADH cofactors. The divergence of pyruvate after glycolysis is pressed during both ethanol production and utilization but as an essential regulatory point in metabolism, which has made it it is expressed in the mitochondria, its primary role is likely to a hotspot for biochemical and industrial research. There are two maintain redox balance (Bakker et al. 2001; de Smidt, du Preez basic directions pyruvate can take at this point: fermentation or and Albertyn 2012). respiration. In most eukaryotes, this is dependent on the pres- ence of oxygen. In aerobic conditions, pyruvate will be converted to acetyl-coA by actions of a pyruvate dehydrogenase and head Ethanol in industry towards the citric acid cycle (Fig. 2). Under fermentative (anaer- obic) conditions, pyruvate is diverted towards fermentation. Ethanol is an important yeast metabolite for most products in- Conversion of pyruvate to ethanol is a two-step process. First, volving yeast fermentation. It is a vital ingredient of fermented pyruvate is converted to acetaldehyde by a pyruvate decarboxy- beverages and is used as a prominent renewable biofuel but lase (PDC), releasing carbon dioxide as waste. There are three ethanol also plays a role in product quality of other fermented confirmed PDC enzymes encoded in the Saccharomyces cerevisiae products where the connection is perhaps more obscure. For genome (Saccharomyces Genome Database; Cherry et al. 2012). example, during baking, ethanol produced by yeast has a These enzymes act as a key metabolic branch point between strong impact on dough extensibility and gluten agglomeration Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S98 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 1. Effect of environmental parameters on ethanol production. Effect on ethanol Parameter Condition production Reference Temperature Above optimal Decrease (lower ethanol Coleman et al. (2007) tolerance) pH Increase Increase (increased Lam et al. (2014) proton electrochemical gradient) Oxygen Increase Increase (higher cell Alfenore et al. (2004) viability) Medium composition Csource Preferred sugars Decrease (undesired Verstrepen et al. (2004) (glucose, sucrose) side effects on physiology) Nsource NH , glutamate Decrease (compared to Albers et al. (1996) amino acids) Metal ions Supplementation Increase Tosun and Ergun (2007) Vitamins Supplementation Increase Alfenore et al. (2002) Lipids (fatty acids, sterols) Supplementation Increase Pham et al. (2010) Nutrient-rich mixtures Supplementation Increase Jones and Ingledew (1994) Potassium Supplementation Increase (increased Lam et al. (2014) potassium membrane gradient) Electric field Application of 15V Increase (alternative Mathew et al. (2015) source of redox power) Enzyme (Amylase) Supplementation Increase (more available Nigam and Singh (1995) sugars) (Jayaram et al. 2014). During cocoa fermentations, the ethanol and oxidizing power (Schievano et al. 2016). Application of a produced by yeast serves as a carbon source for acetic acid bac- static potential of up to 15 V (without any resulting current) to a teria (which are vital for cocoa flavor) and triggers biochemical S. cerevisiae culture resulted in a 2-fold yield of ethanol (reaching reactions within the cocoa bean that lead to the production of 14% v/v) and 2 to 3-fold faster fermentation rate (Mathew et al. various aromas and aroma precursors (Hansen, del Olmo and 2015). In another strategy, Lam et al. (2014) strengthened the op- Burri 1998). posing potassium and proton electrochemical membrane gradi- Given the central role of ethanol in alcoholic fermentation ents during fermentations, which led to an enhanced resistance processes, much research has focused on improving speed and to multiple alcohols, including ethanol (Lam et al. 2014). efficiency of alcohol production by yeasts over the past few decades, especially in the bioethanol industry. Interestingly, there is also an emerging trend towards fermented beverages Genetic factors and ethanol production with reduced ethanol content (Wilkinson and Jiranck 2013;WHO 2014). This is driven by the increasing demand from both con- One of the easiest ways to obtain yeasts with modulated ethanol sumers and producers to reduce problems associated with high production capacity is screening the available natural biodiver- alcohol levels. Too much ethanol can compromise quality of the sity. Most fermentation processes are conducted with S. cere- product and excessive alcohol intake is associated with various visiae, or very related species, such as S. pastorianus (lager beer) health issues. From a financial standpoint, high alcohol content or S. bayanus (some wines). It has been shown numerous times can increase the costs to the consumer in countries where taxes that traits such as ethanol tolerance or ethanol accumulation are calculated based on ethanol content. capacity are strain dependent within S. cerevisiae (Swinnen et al. 2012;Snoek et al. 2015; Gallone et al. 2016) and nature of- ten harbors superior variants. For example, Brazilian bioethanol Environmental parameters and ethanol production plants initially inoculated with baker’s yeasts but were rapidly Modifying the fermentation parameters, including carbon taken over by wild autochthonous strains (Basso et al. 2008). sources, trace elements and even temperature, has proven to be These wild contaminants have been used as commercial starter effective measures for altering ethanol production by industrial cultures ever since. Moreover, while Saccharomyces spp. are still yeasts (Table 1). the preferred organism for most fermentation processes, alter- However, the positive effects of these medium adjustments native species such as Brettanomyces bruxellensis, Metschnikowia are often strain dependent (Remize, Sablayrolles and Dequin pulcherrima, Torulaspora delbrueckii, Saccharomycodes ludwigii and 2000), and in case of food production, the potentially disadvan- Zygosaccharomyces rouxii produce increased (Passoth, Blomqvist tageous side effect on aroma must be assessed carefully. Other, and Schnur ¨ er 2007; Steensels and Verstrepen 2014; Radecka et al. more adventurous, strategies have been recently described. For 2015) or decreased (Contreras et al. 2015;DeFrancesco et al. 2015; example, ‘electro-fermentation’ imposes an electrical field on Morales et al. 2015; Canonico et al. 2016) levels of ethanol, thereby the fermentation to serve as an alternative source of reducing further expanding the portfolio of potential industrial yeasts. Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S99 Nevertheless, numerous research projects have aimed to expression of a non-phosphorylating, NADP -dependent GAP modify ethanol production, or fermentation efficiency in gen- reduces formation of cytosolic NADH and results in decreased eral, within a specific strain by altering the genetic back- glycerol with increased ethanol (Bro et al. 2006). ground. However, the large number of enzymes and branch Lastly, total ethanol accumulation can be improved. This trait points involved can complicate the results of adjusting is related to ethanol tolerance, but different molecular mech- genes and metabolites involved in central carbon metabolism. anisms can underlie them (Pais et al. 2013). Reverse metabolic Ethanol production of industrial strains has been adjusted engineering identified three natural alleles that can improve by various strategies, including increased ethanol tolerance ethanol accumulation capacity in yeast: ADE1 (a nucleotide syn- (Zhao and Bai 2009; Lam et al. 2014;Snoek et al. 2015; thase), URA3 (a decarboxylase involved in pyrimidine synthesis) Voordeckers et al. 2015;Ohta et al. 2016), reduced production of and KIN3 (kinase involved in ethanol tolerance) (Pais et al. 2013). alternative metabolites (e.g. glycerol) (Remize, Sablayrolles and In another study, large-scale, robot-assisted genome shuffling Dequin 2000; Pagliardini et al. 2013; Hubmann et al. 2013a)and yielded hybrids with an increased ethanol accumulation of up to increased ethanol accumulation capacity (Pais et al. 2013;Snoek 7% relative to a widely applied bioethanol strain (Ethanol Red), et al. 2015). but the underlying genetic factors were not identified (Snoek During many industrial fermentation processes, especially et al. 2015). in bioethanol fermentations or high-gravity brewing, yeast en- Some studies aim to reduce ethanol production to fit grow- counter extremely high ethanol concentrations, sometimes ing trends of low alcohol beverages. The main challenge is to reaching up to 20%–25% v/v. This can quickly become toxic achieve the ethanol reduction without the loss of product qual- to the cells and has thus led to considerable efforts in in- ity, as ethanol production is often tightly linked to production creasing ethanol tolerance of industrial yeast strains. There- of other volatile metabolites. Methods for removal of ethanol fore, many studies target the improvement of ethanol toler- during or after the fermentation process exist, however, while ance. Some recent and innovative approaches are highlighted efficient, current strategies are often costly or carry along un- here (see Zhao and Bai 2009; Snoek, Verstrepen and Voordeck- desired side effects, such as inferior aroma (Varela et al. 2015). ers 2016 for a more comprehensive overview). Natural variations Newer strategies aim to limit the amount of ethanol produced in MKT1 (a nuclease), SWS2 (a mitochondrial ribosomal protein) by the yeast, mainly by altering the central carbon flux or reg- and APJ1 (a chaperone with a role in SUMO-mediated protein ulating redox balance (Kutyna et al. 2010; Goold et al. 2017). For degradation), though not traditionally linked to ethanol toler- example, deletion of PDC1 or ADH1, the major ethanol produc- ance, account for the increased ethanol tolerance of the Brazil- tion line, reduces ethanol production (Nevoigt and Stahl 1996; ian bioethanol strain VR1 (Swinnen et al. 2012). Variations in Cordier et al. 2007). Overexpression of glycerol synthesis genes the metabolome, namely accumulation of valine via deletion of such as GPD1 and FPS1 shifts carbon flux away from ethanol and LEU4 and LEU9 (which encode for key enzymes connecting va- towards glycerol synthesis (Nevoigt and Stahl 1996; Remize, Bar- line to leucine synthesis) or reduction of inositol levels by dele- navon and Dequin 2001; Cambon et al. 2006; Cordier et al. 2007). tion of INM2 (involved in inositol biosynthesis), also effectively increase ethanol tolerance (Ohta et al. 2016). Global transcrip- Physiological and ecological roles of ethanol tion machinery engineering, a high-throughput genetic technol- ogy, was used to find variants of the global transcription factor Eukaryotic cells typically opt for respiration when possible as Spt1 with increased ethanol tolerance (Alper et al. 2006). The mu- it offers a higher yield of ATP per molecule of glucose. Cer- tated versions of this protein led to widespread transcriptional tain yeasts, including S. cerevisiae, opt to ferment even in the reprogramming when introduced in yeast, and some of the presence of oxygen (De Deken 1966). This so-called Crabtree resulting mutants demonstrated improved ethanol tolerance effect is paradoxical, as the energy yield is significantly lower. (Alper et al. 2006). Other high-throughput strategies, such as However, it is believed that the rate of ATP production (amount TALENs (transcription activator-like effector nucleases)-assisted per time) is actually higher through fermentation, allowing for multiplex editing and robot-assisted genome shuffling, have faster growth. Moreover, ethanol is highly toxic to most other also yielded improvements in strain ethanol tolerance (Snoek microbes, which may help yeast cells compete with faster- et al. 2015; Zhang et al. 2015c). Long-term evolution has also been growing competitors (Rozpedowska et al. 2011). Although much demonstrated as an effective measure to increase ethanol toler- of metabolic flux is diverted to ethanol, it is important to note ance. Turbidostat cultures grown continuously for over 2 years that a fraction of the carbon is still shuttled to the TCA cycle, with gradually increasing ethanol concentrations yielded toler- which forms important aroma precursors through reactions as- ant variants with mutations in PRT1 (subunit of the eukaryotic sociated with amino acid metabolism. translation initiation factor 3), VPS70 (involved in vacuolar pro- Ethanol production by fermenting yeast cells may also have tein sorting) and MEX67 (poly(A)RNA-binding protein involved in an indirect role in ecology. Several studies indicate that ethanol nuclear mRNA export) (Voordeckers et al. 2015). influences the behavior of insects that inhabit the same nat- Modification of glycerol synthesis can also affect ethanol pro- ural niches. Fruit flies are strongly attracted to rotting fruits duction. During anaerobic growth, glycerol serves as an ‘elec- due to high concentrations of fermentation products, including tron sink’ to re-oxidize NADH generated during biosynthesis ethanol (Becher et al. 2012). In fact, ethanol provides a nuanced and concentrations can reach up to 5 g/L during industrial fer- signal for preferential oviposition sites among closely related mentations (Nielsen et al. 2013). Deletion of glycerol synthesis Drosophila (Diptera: Drosophilidae) species. Ethanol tolerance of genes GPD1 and GPD2 directly decreases glycerol levels with a adult flies of different species seems to correlate with preference resultant increase in ethanol (Nissen et al. 2000). Natural varia- for ethanol-rich oviposition substrate (Sumethasorn and Turner tions of GPD1, HOT1 (a transcription factor involved in glycerol 2016). Drosophila melanogaster is highly ethanol tolerant and in synthesis), SSK1 (a phosphorelay protein involved in osmoreg- laboratory conditions will lay twice as many eggs on ethanol- ulation) and SMP1 (a transcription factor involved in osmotic rich media than the ethanol-sensitive D. mauritiana.Moreover, stress response) also result in decreased glycerol to ethanol ra- the same species from differing climates can demonstrate vari- tios during fermentation (Hubmann et al. 2013a,b). Additionally, ations in both ethanol tolerance and ovipositioning preference. Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S100 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Drosophila melanogaster from temperate populations, such as Eu- volatiles that make them more attractive to potential ani- rope, has higher ethanol tolerance than populations from Africa mal pollinators. The nectar of bertam palm (Eugessona tristis), (Zhu and Fry 2015) and higher ethanol concentrations increase a popular food source for several insects and small animals, ovipositioning frequency from the European fly, but reduced fre- can contain up to 3.8% ethanol (Wiens et al. 2008). Behavioral quency from African flies (Sumethasorn and Turner 2016). studies indicate that these nectar-seeking animals, specifically The effect of ethanol content on ovipositioning has also been the primate slow loris (Nycticebus coucana) and the lemur aye- linked to the presence of parasitic wasps. Drosophila melanogaster aye (Daubentonia madagascariensis), preferentially feed on nec- increases egg laying on ethanol-rich substrate when there are tar containing ethanol (Gochman, Brown and Dominy 2016). parasitic wasps in the vicinity (Kacsoh et al. 2013). Subsequently, Interestingly, aye-ayes have a mutation in their ADH4 gene eggs laid by the wasps suffer increased mortality if the host in- resulting in a 40-fold increase of their ethanol metabolism gests ethanol-rich substrates (Milan, Kacsoh and Schlenke 2012) compared to most of the primates, potentially explaining why and even dilute levels of ethanol can reduce the total number of they do not get intoxicated on the high-alcohol food (Carrigan parasitoid eggs laid in the larvae. The preference for an ethanol- et al. 2015). containing ovipositioning site can strongly depend on the presence of suitable, ethanol-free food sources nearby. When the alternative ethanol-free substrate is close, flies prefer the PRIMARY FERMENTATION METABOLITES: CO , ethanol-containing substrate. As distance increases, prefer- ACETALDEHYDE AND ACETIC ACID ence for the ethanol rapidly declines (Sumethasorn and Turner Biochemistry of CO , acetaldehyde and acetic acid 2016). Taken together, this suggests that fruit flies are contin- production uously reevaluating the relative positions of the available sub- strates, potentially to ensure survival. They seem to prefer harsh As mentioned, under fermentative (anaerobic) conditions, pyru- (ethanol-rich) environments to protect the eggs and freshly vate is diverted towards ethanol in a two-step process (Fig. 2). hatched larvae, but only if a suitable, less harsh food source is Pyruvate is first converted to acetaldehyde with concomitant re- nearby for the larvae to find. lease of carbon dioxide (CO ) by PDC. The two major PDC en- The use of microbially produced compounds is a relatively re- zymes, Pdc1 and Pdc5, are the major contributors to the de- cent and recurrent approach currently being used as attractants carboxylation activity in the cell and therefore directly con- for various biological pests, and several examples will appear trol levels of acetaldehyde and CO (Kulak et al. 2014). Pdc6 throughout this review. One very recent example of this tactic is primarily utilized during growth on non-fermentable carbon is the use of ethanol-containing mixtures against the avian par- sources (Hohmann 1991). One would expect then that in a PDC1 asite Philornis downsi (Diptera: Muscidae). This South American- deletion the levels of acetaldehyde to significantly drop. How- native fly has recently invaded the Galapagos and its larvae have ever, in certain conditions, deletion of this enzyme demon- been feeding on the nestlings of the famous Darwin’s finches strates an increase in acetaldehyde (Curiel et al. 2016). It is hy- (Kleindorfer and Dudaniec 2016). Philornis downsi adults feed on pothesized that Pdc5 can compensate for up to 70% of the re- fermented substrates, and ethanol plays a crucial role in guiding quired PDC activity, indicating a possible compensatory mech- them to the food source. When ethanol is mixed with acetic acid, anism to maintain flux towards acetaldehyde and subsequent it effectively and specifically attracts P. downsi over non-target ethanol production (Wang et al. 2015). Furthermore, Pdc5 has insects (Cha et al. 2016). Similarly, the combination of ethanol a higher specific activity which may allow it to directly com- and acetic acid has been suggested as a useful and inexpensive pete with the respiratory pyruvate dehydrogenase and may help lure for trapping other insects such as pathogen-carrying Mus- push more pyruvate towards ethanol (Agarwal, Uppada and cina stabulans (Diptera: Muscidae) and Fannia canicularis (Diptera: Noronha 2013). Muscidae) (Landolt, Cha and Zack 2015), as well as the corn pest Acetaldehyde can then continue towards ethanol via ADH ac- Carpophilus humeralis (Coleoptera: Nitidulidae) (Nout and Bartelt tivity, or it can be acted on by an aldehyde dehydrogenase (ALD) 1998). to produce acetic acid. Like the ADHs, there are several ALDs, Insects are not the only organisms to be affected by ethanol. further expanding the level of regulation centered around car- Originally thought to be solely soil dwelling, the nematode bon flux. If acetaldehyde is produced cytosolically, it can be acted Caenorhabditis elegans is frequently found in rotting fruits, stems on by Ald6 or Ald2; if produced in the mitochondria, it is con- and flowers (F elix and Braendle 2010). It is therefore likely that verted by Ald4 or Ald5. Additionally, an acetaldehyde molecule C. elegans larvae encounter ethanol from microbial fermenta- still covalently linked to the PDC complex (via the bound thi- tion in its natural environment. While high concentrations of amine pyrophosphate) can interact with an additional acetalde- ethanol (above 100 mM) result in slower development, decreased hyde to form acetoin (Fig. 2). fertility and shorter life span (Davis, Li and Rankin 2008), at lower concentrations, ethanol appears to have beneficial survival ef- fects, prolonging the lifespan of the stress-resistant larval stage Carbon dioxide in industry (Castro et al. 2012). Since the nematode larvae do not appear to actively seek out ethanol (Patananan et al. 2015), it is hypothe- While humans do not typically associate an odor with carbon sized that the ethanol could provide a temporary carbon source dioxide, its production is important in some industrial pro- to ensure the larvae survive until proper food sources are found. cesses and is detectable by other organisms (see Physiological Interestingly, ethanol can influence C. elegans negatively through roles of CO ). CO is responsible for the natural carbonation of 2 2 a complex multispecies interaction: the yeast-produced ethanol fermented beverages and adequate gas production is arguably can enhance the growth of several Acinetobacter species, and in the most important selection criterion for commercial baker’s turn make them more efficient to withstand and even kill their yeasts, as proper leavening requires rapid and sufficient CO natural predator, C. elegans (Smith, Des Etages and Snyder 2004). release (Randez-Gil, Cor ´ coles-Saez ´ and Prieto 2013). Therefore, Certain primates are also attracted to fermenting food. Com- most optimization for increased speed of CO production has plex microbial communities in nectar sources produce diverse been performed in bread yeasts. Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S101 Environmental parameters and CO production with improved freeze tolerance, without undesirable side effects in other fermentation properties (Teunissen et al. 2002). Most bread fermentations should only take 1–2 h which requires a quick onset of the fermentation process to rapidly and ef- Acetaldehyde and acetic acid in industry fectively produce large volumes of CO .Tothisend,various dough parameters can be adjusted to speed up CO production Acetaldehyde is the central intermediate between pyruvate and (Table 2). Optimization of the physiological state of the yeasts ethanol but it is also an important aroma compound. It is quan- before introducing them into the dough can drastically improve titatively the most abundant aldehyde in most fermented prod- leavening ability. This can be accomplished by pre-soaking and ucts including apple juice and spirits (Miyake and Shibamoto thus reactivating dry yeast prior to starting the bread fermenta- 1993), beer (Margalith 1981; Adams and Moss 1995), cider and tion (Gelinas 2010). Additionally, adjusting the way that the dried perry (Williams 1975), wine (Liu and Pilone 2000), cheese (Engels yeasts are produced, for example, by optimizing the medium in et al. 1997), yoghurt (Zourari, Accolas and Desmazeaud 1992)and which they are grown, the timing at which the yeast cells are ripened butter (Lindsay, Day and Sandine 1965). Production of harvested, or the specific drying protocol, can increase yeast via- acetaldehyde has direct influence on the final product’s aroma, bility and vitality during bread fermentations (Galdieri et al. 2010; levels of ethanol production, as well as product stability and tox- Rezaei et al. 2014). icology (Romano et al. 1994). At low levels, acetaldehyde provides a pleasant, fruity aroma and is a decisive aromatic compound of many sherry-type and port wines (Zea et al. 2015). However, it Genetic factors and CO production is also notorious for its undesirable green apple-like or grassy In general, the ability to ferment specific bread-associated sug- flavor when exceeding threshold levels. This threshold varies ars (namely maltose, glucose, sucrose, and fructose) has been drastically between matrices, with 10 μg/g (ppm) reported for alteredtoimprove CO production, or the leavening ability, of beer (Meilgaard 1982), 30 μg/g for cider (Williams 1974)and up baker’s yeast. One of the most common problems associated to 130 μg/g for certain wines (Berg et al. 1955). Chemical conver- with dough fermentation is the considerable lag between fer- sions during aging can also increase overall acetaldehyde con- mentation of preferred sugars, glucose and sucrose, and fer- centrations of fermented beverages over time (Vanderhaegen mentation of maltose, the principle fermentable sugar in bread et al. 2003). dough. Catabolite repression slows down the switch and sub- Apart from its direct effect on flavor, acetaldehyde arguably sequently lengthens leavening time (Gancedo 1998). Therefore, has even a more important role indirectly. The molecule is ex- genes associated with glucose repression and maltose utiliza- tremely reactive and can react with various other compounds. tion have often been strategically targeted for genetic mod- In red wines, for example, acetaldehyde influences various pa- ification (Osinga et al. 1989;Sun et al. 2012;Lin et al. 2014, rameters not directly linked to aroma. It can bind sulfur dioxide 2015b; Zhang et al. 2015a,b). Alternatively, maltose utilization (SO ), which drastically reduces the effectiveness of this antimi- can be improved by selecting mutants on medium containing crobial agent, thereby facilitating spoilage (Liu and Pilone 2000). fermentable maltose with non-metabolizable glucose analogs. Acetaldehyde can also react with tannins, which are naturally Such strategies yield strains with deficiencies in catabolite re- occurring polyphenols in grapes, to form irreversible, covalent pression that could co-consume glucose and maltose resulting bridges, resulting in a reduction of the dry, puckering mouth- in faster dough leavening (Randez-Gil and Sanz 1994;Rincon ´ feel (‘astringency’) that is associated with these compounds et al. 2001; Salema-Oom et al. 2011). Similar mutants could po- (Mercurio and Smith 2008). A similar condensation reaction be- tentially reduce the lag time in the beer brewing fermentations tween anthocyanins or between anthocyanins and tannins me- as well (New et al. 2014). Consecutive rounds of mass mating and diated by acetaldehyde-bridged complexes is observed, result- selection have also yielded commercial strains with improved ing in polymeric pigments that influence wine color. These maltose utilization (Higgins et al. 2001). highly stable complexes are not susceptible to SO bleaching Yeast encounter various severe stresses during bread fer- or changes in wine pH, and are therefore desired for color sta- mentations, such as high sugar and salt concentrations, which bility (Boulton 2001). Similarly, interactions between the antho- reduces their performance (Aslankoohi et al. 2013). Improve- cyanin malvidin 3-monoglucoside and catechins in the presence ments of general stress resistance of industrial yeast have been of acetaldehyde, which also influence color and color stability in shown to yield faster bread fermentations. This is generally red wine, were observed (Rivas-Gonzalo, Bravo-Haro and Santos- achieved by increasing production of glycerol and other small Buelga 1995). The central role of acetaldehyde in these reactions protective molecules such as proline and trehalose (Shima and even inspired researchers to experiment with exogenous addi- Takagi 2009). Overexpression of glycerol synthesis genes, such tion of acetaldehyde, yielding red wines with reduced astrin- as GPD1, increases glycerol accumulation and subsequent osmo- gency and more stable color (Sheridan and Elias 2015). tolerance (Aslankoohi et al. 2015). Modification of proline perme- Acetic acid is referred to, in industry, as volatile acidity ases (PUT4) or proline biosynthesis genes (PRO1) increases pro- or vinegar taint. While industrial Saccharomyces species can line accumulation and improves osmo-, cryo- and halotolerance produce acetic acid, the presence of high acetic acid concen- (Kaino et al. 2008; Poole et al. 2009; Sasano et al. 2012). Disrup- trations often indicates the presence of other species. High tion of trehalose degradation (NTH1, ATH1) or efflux ( FPS1)in- levels of acetic acid are typically associated with the respira- creases intracellular trehalose levels and improves freeze tol- tory metabolism of ethanol by acetic acid bacteria. However, erance (Shima et al. 1999;Izawa et al. 2004; Sasano et al. 2012; some yeasts, notably Brettanomyces spp., can produce acetic Sun et al. 2016). Overexpression of CAF16 and ORC6,two genes acid in aerobic conditions (Crauwels et al. 2015). This trait is that are upregulated during osmotic and cryostress, also im- highly strain and species dependent (Castro-Martinez et al. 2005; proves overall stress tolerance of the yeast during baking (Per ´ ez- Rozpedowska et al. 2011). One species, Brettanomyces bruxellensis, Torrado et al. 2010). Directed evolution has also been used to im- is so efficient at producing acetic acid, it has been proposed as a prove stress tolerance in baker’s yeast. Ultraviolet mutagenesis candidate organism for industrial production (Freer 2002; Freer, followed by 200 consecutive freeze–thaw cycles yielded mutants Dien and Matsuda 2003). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S102 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 2. Effect of environmental parameters on CO production. Parameter Condition Effect on CO production Reference Temperature Decrease storage T of Decrease Sasano et al. (2012) yeasted dough Dough mixing time Increase Increase Sahlstrom ¨ et al. (2004) Medium composition C source availability Increase Increase, however, risk for Sahlstrom ¨ et al. (2004) osmotic stress Salt Increase Decrease (stress), however, Lynch et al. (2009), Toyosaki better CO containment and Sakane (2013) Nutrient mixes (wheat bran) Supplementation Increase Hemdane et al. (2016) Enzyme (amylase) Supplementation Increase (more available Struyf et al. (2017) sugars) In specific cases, the presence of these acid-producing tathione (Chen et al. 2012), oxidation of acetaldehyde to acetic species is desired for the fermentation, but more commonly acid (Yao et al. 2012) or increasing pyruvate flux into the mito- acetic acid is a sign of spoilage. In wine, 0.2–0.4 g/L of acetic chondria (Agrimi et al. 2014; Bender, Pena and Martinou 2015; acid is acceptable, but above 1.2–1.3 g/L, it is considered a fault. Jayakody et al. 2016) has been shown to reduce levels of ac- In contrast, concentrations up to 1.5 g/L are common in Lambic etaldehyde. Strains selected for resistance to Adh2 inhibitor 4- beers and, in combination with bacterially produced lactic acid, methylpyrazole demonstrated decreased ADH2 expression and are crucial for the sour characteristics of Lambic (Witrick 2012). an 82% reduction in acetaldehyde production (Wang et al. 2013). Similarly, direct disruption of ADH2 reduces acetaldehyde by 68% (Wang et al. 2006). Environmental parameter effects on acetaldehyde and Reduction of volatile acidity is mainly a concern in the wine acetic acid production industry. Aerobic fermentation can cause excess levels of acetic High levels of acetaldehyde are undesirable in an industrial acid. Due to the complexity of this part of the metabolic path- context and some simple adjustments to fermentation param- way, direct disruption of associated genes can have multiple and eters have been suggested to alter the level of acetaldehyde sometimes undesired effects. Deletion of PDC1 or ALD6 can re- (Table 3). For example, acetaldehyde production in some wine duce acetate levels but significantly increases levels of acetalde- strains remains constant when fermented between 12 Cand hyde, limiting its applicability (Luo et al. 2013; Curiel et al. 2016). ◦ ◦ 24 C but drastically increases at 30 C (Romano et al. 1994). Sup- The previously mentioned overexpression of GPD1 effectively plementation of SO2 also induces acetaldehyde production, but decreases ethanol production but also leads to excessively high the underlying mechanisms are unknown (Herraiz et al. 1989; acetic acid levels in wine (Cambon et al. 2006). Combining this Herrero, Garc´ıa and D´ıaz 2003). overexpression with deletion of ALD6 reduces the acetic acid Since acetic acid has different sources in fermented bever- but also increases acetaldehyde and acetoin. This can be com- ages (yeast and bacteria), there are different strategies for tar- pensated by overexpression of BDH1, which diverts the excess geting its production. Here we focus on control of yeast-derived acetaldehyde and acetoin to 2,3-butanediol, which has no ef- acetic acid from two important yeast genera associated with fect on overall flavor and aroma (Fig. 2)(Ehsani et al. 2009). Less industrial fermentations (Table 3). Production by Brettanomyces direct approaches require less genetic compensation. For ex- can be controlled by reducing oxygen availability (Rozpedowska ample, deletion of AAF1, a transcriptional regulator of the ALD et al. 2011), supplementing the fermentation with antimicro- genes, reduces acetic acid levels without affecting acetaldehyde bial agents (Portugal et al. 2014) or applying electric currents production (Luo et al. 2013). Strains with mutations in YAP1,a (Zuehlke, Petrova and Edwards 2013). Production by Saccha- transcription factor involved in oxidative stress tolerance, also romyces can be reduced by promoting general growth. Acetic demonstrate reduced acetic acid levels (Yamamoto et al. 2000; acid production is driven by accumulation of NAD during glyc- Cordente et al. 2013). erol production (Eglinton et al. 2002) and increasing biomass (i.e. growth) can help regenerate the pool of NADH. Supplementation Physiological and ecological roles of CO , acetaldehyde of nitrogen or unsaturated fatty acids can promote yeast growth and acetic acid with a subsequent reduction in acetic acid (Varela et al. 2012). Re- Though not a distinguishable aroma for humans, other or- ducing glycerol production by lowering the sugar concentration ganisms have distinct sensory responses to carbon dioxide. In can also decrease the levels of acetic acid in the final product yeast populations, including S. cerevisiae,CO can mediate cell– (Bely, Rinaldi and Dubourdieu 2003). 2 cell interactions, inducing growth and budding of neighboring colonies (Volodyaev, Krasilnikova and Ivanovsky 2013). In Can- Genetic factors and acetaldehyde and acetic acid dida albicans, increasing concentrations of self-generated CO production causes the cells to undergo morphological changes and switch Given the central role of acetaldehyde in carbon metabolism to hyphal growth (Hall et al. 2010). Interestingly, this mechanism (Fig. 2), it is not a straightforward task to specifically modu- has been implicated in the pathogenicity of C. albicans,asthe late its production. However, attenuation of ethanol metabolism switch to filamentous growth is important for biofilm formation (Wang et al. 2013), increasing acetaldehyde scavenging via glu- and invasive growth in the host (Hall et al. 2010;Lu et al. 2013). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S103 Table 3. Effect of environmental parameters on acetaldehyde, and acetic acid production. Effect on acetaldehyde Parameter Condition production Reference Temperature Increase Increase Romano et al. (1994) Oxygen Increase Increase Branyik et al. (2008), Curiel et al. (2016) Medium composition Csource Non-fermentable Increase Romano et al. (1994) SO Increase Increase Jackowetz et al. (2011) Effect on acetic acid production Brettanomyces Oxygen Increase Increase (direct effect on Rozpedowska et al. (2011) production) Medium composition Antimicrobial agents (sulfite, chitosans, ...) Supplementation Decrease (inhibits growth) Portugal et al. (2014) Weak acids and sorbic acid Supplementation Decrease (inhibits growth) Wedral et al. (2010) Low electric current Application of ∼200 mA Decrease (inhibits growth) Zuehlke et al. (2013) Pulsed electric field Application of ∼30 Decrease (inhibits growth) Zuehlke et al. (2013) kV/cm, 1–4 μs pulses Saccharomyces Temperature Decrease Decrease Beltran et al. (2008) Oxygen Increase Increase Curiel et al. (2016) Medium composition C concentration Increase Increase (glycerol Bely et al. (2003) production, redox imbalance) Nsource Supplementation Decrease (stimulates yeast Bely et al. (2003), Barbosa growth, provides NADH) et al. 2009 Copper Supplementation Increase Ferreira et al. (2006) Yeast lees and insoluble material Increase Variable (some lead to Delfini and Costa ( 1993) increase, others to decrease) Accumulation of acetaldehyde in yeast cells results in growth 2004; Turner and Ray 2009). Recent studies indicate that this re- inhibition and a stress response (Stanley et al. 1993; Aranda and pulsion highly depends on the behavioral context, i.e. whether Olmo 2004). When acetaldehyde diffuses out of the cell, it acts the flies are walking on surface or flying in the air (Wasserman, as a volatile signaling molecule. At high cell densities, yeast cells Salomon and Frye 2013). When in flight, Drosophila melanogaster coordinate their metabolism by sensing the secreted acetalde- are attracted to CO , possibly due to modulations of neurotrans- hyde, resulting in collective macroscopic oscillations and syn- mitters which occur during flight (Orchard, Ramirez and Lange chronized phases of growth (Richard et al. 1996). Interestingly, 1993). The current hypothesis is that in crowded conditions, several cellular systems, from yeast colonies to human muscle, when flies are gathered on a surface, CO is repulsive but when and even tumors, demonstrate this type of synchronized oscil- in flight and searching for food, CO can act as an attractive sig- lations of glycolytic reactions (Betz and Chance 1965; Tornheim nal to indicate the presence of fermenting fruits. and Lowenstein 1974; Nilsson et al. 1996;Richard 2003;Fru et al. Acetic acid is also an important volatile for mediating the 2015). behavior of D. melanogaster. This fruit fly is reported to have a Acetic acid is potentially used by Brettanomyces as a strat- highly selective olfactory neuron for detection of acids which egy to outcompete other microbes (Rozpedowska et al. 2011). is generally connected with observed acid-avoiding behavior The ‘make-accumulate-consume’ strategy allows Brettanomyces (Ai et al. 2010). However, D. melanogaster is also known to be lured yeast to accumulate high levels of acetic acid which dramatically by acetic acid (Hutner, Kaplan and Enzmann 1937; Knaden et al. lowers the pH of the environment. Since this yeast has a higher 2012), which accounts for its attraction to vinegar and nickname tolerance for low pH than most microbes, it can withstand the as the ‘vinegar fly’. Females looking for ovipositioning sites are extreme environment and later consume the acetic acid as an strongly attracted by acetic acid, whereas flies not ready to de- extra carbon source. posit eggs show little or no attraction (Joseph et al. 2009;Gou These three compounds also play an important role in in- et al. 2014). The closely related species, D. simulans,isrepulsed sect behavior. Acetaldehyde is a core component of a compound by microbially produced acetic acid; this behavior strongly corre- blend used to attract and trap pest beetles from the genus Car- lates with the increasing acid concentration (Gunther ¨ et al. 2015). pophilus (Phelan and Lin 1991; Nout and Bartelt 1998). In sev- These examples suggest a complexity in the perception and pro- eral reports, CO had a repulsive effect on fruit flies (Suh et al. cessing of sensory information, both gustatory and olfactory, 2 Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S104 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 3. Production of vicinal diketones. The vicinal diketones are produced as by-products during the isoleucine-leucine-valine (ILV) biosynthetic pathways. Gene names correlate with nomenclature from S. cerevisiae (Saccharomyces Genome Database). OYE = ‘Old Yellow Enzyme’. Dotted lines indicate import/export, solid lines indicate biochemical reactions. Note: dotted line from sugar to pyruvate also encompasses glycolysis. to modulate behavior. In this example, it has been hypothe- of acetohydroxybutyrate forms 2,3-pentanedione. Towards the sized that the egg-laying preference on acetic acid-containing end of fermentation, these compounds can be reabsorbed by the substrates depends on gustatory inputs (females will taste the cell and converted to acetoin (and subsequently 2,3-butanediol) acetic acid when on the surface). However, when not in direct and 3-hydroxy-2-pentanone by various reductases (van Bergen contact with the medium, olfactory information only leads to et al. 2016). aversion of acetic acid-containing food (Joseph et al. 2009). To- gether with ethanol, acetic acid has also been found as an im- portant volatile to attract flies such as Fannia canicularis, Muscina Vicinal diketones in industry stabulans and Philornis downsi (Diptera: Muscidae) to fermenting substrates as a food source (Landolt, Cha and Zack 2015; Cha Vicinal diketones can provide a pleasant nutty, toasty and toffee- like flavor in fermented foods and beverages, most notably beer, et al. 2016). Furthermore, when acetic acid is combined with other fermentation compounds, such as phenylacetaldehyde, wine and dairy products (Molimard and Spinnler 1996;Bar- towsky and Henschke 2004; Krogerus and Gibson 2013a). How- stronger attraction of insects is achieved (Becher et al. 2010, 2012; Cha et al. 2012). ever, they are considered off-flavors when present in high con- centrations, changing their sensory perception to ‘buttery’ or ‘rancid’. Especially in beer brewing, vicinal diketone production AMINO ACID METABOLITES: VICINAL is an ongoing challenge. Diacetyl is rarely perceived positively DIKETONES in beer, except in a few specific styles (e.g. sour ales, Bohemian Pilsner and some English ales). Biochemistry of vicinal diketone production Diacetyl is generally more of a focus in industrial beer fer- mentation than 2,3-pentanedione for two reasons. First, it has Vicinal diketones (i.e. compounds containing two adjacent a significantly lower sensory threshold (0.1 μg/g versus 1.0 μg/g) carbon-oxygen double bonds) can be produced during fermen- which makes it more detectable in the final product. Second, the tation through non-enzymatic decarboxylation of intermediates direct connection between diacetyl and pyruvate has implica- in the valine and isoleucine anabolic pathways (Fig. 3). Dur- tions in managing ethanol production levels. In wine, diacetyl is ing fermentation, pyruvate can be converted to various carbon considered less of a problem and low (1–4 μg/g) concentrations compounds such as acetolactate. The acetolactate can then be positively contribute to desirable buttery or butterscotch notes. diverted towards synthesis of valine and leucine. Inefficiency Moreover, excessively high concentrations are rare but rather in- of the valine biosynthesis pathway during growth results in a dicate bacterial spoilage or other irregularities during malolactic buildup of acetolactate which is then secreted into the medium. fermentation (Bartowsky and Henschke 2004). Additionally, di- Similarly, during isoleucine biosynthesis, acetohydroxybutyrate acetyl is masked in part by the presence of SO in wine which is produced and is also secreted. Both compounds are non- 2 results in a marked increase in threshold levels (Bartowsky and enzymatically converted to diketones: decarboxylation of aceto- Henschke 2004). lactate forms diacetyl (2,3-butanedione) while decarboxylation Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S105 Table 4. Effect of environmental parameters on vicinal diketone production. Parameter Condition Effect on vicinal diketone production Reference Temperature Increase Decrease during fermentation or Bamforth and Kanauchi (2004) maturation (higher cell density, more acetolactate to diacetyl conversion) pH Decrease Increase (increased enzyme efficiency) Bamforth and Kanauchi ( 2004) Fermentation time Increase Decrease (more acetolactate to Bamforth and Kanauchi (2004) diacetyl conversion and diacetyl reduction) Oxygen Increase Decrease (higher cell density) Portno (1966) Medium composition Valine supplementation Increase Decrease (less acetolactate Krogerus and Gibson (2013b) production, see Figure 2) Sugar concentration Increase Decrease Saerens et al. (2008b) Enzyme (α-Acetolactate decarboxylase) Supplementation Decrease (acetolactate to acetoin Godtfredsen and Ottesen (1982) conversion) Environmental parameters and vicinal diketone 2012). Heterologous expression of a bacterial acetolactate decar- boxylase gene (ALDC) catalyzes the non-oxidative decarboxyla- production tion of acetolactate to acetoin and bypasses diacetyl production Due to the highly reductive conditions that exist at the end of (Kronlof and Linko 1992). alcoholic fermentations, the concentration of diacetyl is usu- ally below (or close to) its sensory detection threshold in fresh Physiological and ecological roles of vicinal diketones beer (Haukeli and Lie 1972). Diacetyl reduction effectively elimi- nates the undesired flavors as acetoin and 2,3-butanediol do not As described, production of the vicinal diketones is done ex- contribute to the aroma profile. Therefore, some beers are sub- tracellularly following the secretion of accumulated acetolac- jected to a maturation phase of 2–3 weeks after fermentation tate and acetohydroxybutrate. The biological role of this phe- to allow any residual acetolactate to decarboxylate and subse- nomenon is not known, but protection from carbonyl stress and quently be reduced by the yeast to below its detection limit. subsequent cellular damage has been suggested (van Bergen This maturation phase requires storage capacities and limits et al. 2016). Additionally, the reduction of the diketones is phys- the output of beer from a brewery and the economic feasibil- iologically favorable for yeast, as the resulting end products are ity. Therefore, there have been some considerable efforts to find + + less toxic and the reactions replenish the NAD and NADP alternative ways to reduce natural diacetyl formation or speed pools (De Revel and Bertrand 1994). up diacetyl reduction by modifying various process parameters Diacetyl has a ‘masking’ role in ecological settings rather (Table 4). than a direct role as a signaling molecule. Drosophila melanogaster The connection to amino acid metabolism directly affects has high specificity neurons for detecting diacetyl and CO synthesis of these two compounds; if nitrogen is low and the (de Bruyne, Foster and Carlson 2001). As discussed earlier, cell needs to synthesize its amino acids, production of these CO can elicit avoidance behavior in fruit flies, which seems by-products will also increase (Krogerus and Gibson 2013a). somewhat counterintuitive, since CO is a signal of ferment- Simply supplementing fermentation media with exogenous va- ing fruit, a suitable food source and ovipositioning site. Diacetyl line can dramatically decrease production of diacetyl (Krogerus masks the avoidance signal by blocking the receptor, result- and Gibson 2013b). Since the conversion of acetolactate to di- ing in attraction to the fermentation source (Turner and Ray acetyl is non-enzymatic, heating after fermentation increases 2009; Turner et al. 2011). A reversed interplay is observed in the rate of conversion of excess acetolactate, which can subse- several mosquito species, where mosquitoes are attracted to quently be reduced (Kobayashi et al. 2005). The use of a contin- CO which is then blocked by the presence of diacetyl (Turner uous fermentation setup minimizes yeast growth, and thus va- et al. 2011). line biosynthesis, and reduces formation of diacetyl (Verbelen et al. 2006). AMINO ACID METABOLITES: HIGHER Genetic factors and vicinal diketone production ALCOHOLS Perhaps the most well-characterized biochemical pathway in Arguably one of the most promising and cheaper strategies to re- yeast aroma production is the Ehrlich pathway. This is likely due duce vicinal diketones is modification of yeast metabolism. Most to the very desirable and recognizable compounds produced by commonly, this is done by increasing the metabolic flux from this pathway—the higher (fusel) alcohols and subsequently, the acetolactate to valine or promoting conversion of acetolactate acetate esters. Felix Ehrlich first posited the connection between to acetoin. Mutation of ILV2 (acetolactate synthase) reduces di- amino acid metabolism and higher alcohol formation in 1907 acetyl formation by 64% (Wang et al. 2008). Similarly, increased based on their structural similarity (Fig. 4). This led to a sim- expression of ILV5 (acetohydroxyacid reductosiomerase), the ple, classic experiment of varying the concentration of specific rate-limiting step in valine synthesis, reduces diacetyl forma- amino acids in the fermentation media and noting changes in tion 50%–60% (Mithieux and Weiss 1995; Kusunoki and Ogata Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S106 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 4. The Ehrlich pathway. There are several routes that can direct carbon compounds into the production of amino acids and subsequently the higher alcohols. This scheme depicts the most direct connections between the amino acids and the respective higher alcohols through the three-step Ehrlich Pathway (general reactions depicted at top). Dotted lines indicate multiple steps. Note: the reduction step can be carried out by over 10 different enzymes which vary in localization, regulation and substrate specificity; AdhX = alcohol dehydrogenase (Adh1, Adh2, Adh3, Adh4, Adh6, Adh7); AadX = aryl alcohol dehydrogenase (Aad3, Aad4, Aad6, Aad10, Aad14, Aad15, Aad16). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S107 production of the corresponding fusel alcohols (Ehrlich 1907). Reduction Over the next century, the details of this biochemical process At this point, the fusel aldehydes can undergo an oxidation or have been greatly uncovered leading to significant improve- a reduction. The various ADHs and AADs catalyze the reduc- ments in the fermentation industry. tion step and complete the Ehrlich pathway. Any one of the ADH enzymes can catalyze this last step, but research indicates that Adh1 and Adh2 mainly participate in ethanol metabolism (de- scribed above). If the fusel aldehydes undergo an oxidation re- Biochemistry of higher alcohol production action by an ALD, they are converted into their respective fusel The Ehrlich pathway is a three-step process that modifies assim- acids. ilated amino acids, the major source of nitrogen in many fer- mentation processes. In general, amino acids are deaminated, Higher alcohols in industry decarboxylated and finally reduced to their respective alcohol derivatives (Fig. 4). By sequentially modifying amino acids, yeast Higher alcohols can impart a much-desired effect on the prod- cells can harvest and utilize the essential nitrogen as needed uct’s flavor despite their higher sensory threshold, which can and in turn produce an array of fragrant and distinct aroma com- differ several orders of magnitude compared to their corre- pounds (Hazelwood et al. 2008;Pires et al. 2014). Given the chem- sponding acetate esters. The major fusel alcohols found in al- ical similarities of the intermediates to pyruvate, acetaldehyde, coholic beverages are 1-propanol (alcoholic aroma), 1-butanol and ethanol, many of the same enzymes involved in production (alcoholic), isobutanol (alcoholic), 2-phenylethanol (roses, flow- of the primary fermentation metabolites are also involved in this ery) and isoamyl alcohol (banana, fruity). pathway. The rose-like fragrance of 2-phenylethanol has made it a desirable compound for use in many perfumes, cosmetics and beverages (Etschmann et al. 2002). Currently, the greater part Transamination of its commercial production is done synthetically, but this After uptake from the media, amino acids are converted to their process requires use of carcinogenic precursors, such as ben- respective α-keto acid by a transaminase capable of transferring zene and styrene, and yields various difficult-to-remove by- amine groups between amino acids. In Saccharomyces cerevisiae, products. It is possible to extract 2-phenylethanol from the es- there are six enzymes capable of this type of reaction: Bat1, sential oils of plants, but this process is excessively expen- Bat2, Aat1, Aat2, Aro8 and Aro9 (SGD, Cherry et al. 2012). Aat1 sive due to low yields (Etschmann et al. 2002). Therefore, re- and Aat2 do not play a role in higher alcohol production; these searchers have turned to microbial production of this compound enzymes act specifically on aspartate as part of the malate- (Carlquist et al. 2015). Genetically modified or mutagenized aspartate shuttle to move electrons from the cytosol to the mi- Saccharomyces cerevisiae strains have been utilized to convert tochondria for respiratory energy production (Cronin et al. 1991; phenylalanine into 2-phenylethanol, typically by enhancing the Morin, Subramanian and Gilmore 1992). The other four enzymes Ehrlich pathway (Kim, Cho and Hahn 2014). Non-conventional have been directly linked to higher alcohol synthesis but, as seen yeasts have also been explored as production strains includ- with the ADHs discussed above, each contributes differently to ing Kluyveromyces marxianus, which naturally produces more 2- the Ehrlich pathway. Bat1 and Bat2 are primarily involved with phenylethanol than S. cerevisiae (Ivanov et al. 2013). Additionally, transamination of the branched chain amino acids, whereas K. marxianus grows quickly and is thermotolerant making it an Aro8 and Aro9 are aromatic amino acid transaminases acting on interesting candidate for commercial production (Etschmann, phenylalanine and tryptophan, respectively (Kispal et al. 1996; Sell and Schrader 2003; Gao and Daugulis 2009; Morrissey et al. Iraqui et al. 1998). 2015). The associated fusel acids are also of industrial interest. The production of these compounds can be perceived posi- Decarboxylation tively or negatively depending on the context. In soy sauce, The second step of the Ehrlich pathway is the irreversible de- flor-forming strains of Zygosacharomyces rouxii can produce carboxylation of the α-keto acid to an aldehyde. The same three 2-methylpropanoic acid (isobutyric acid) and 3-methylbutanoic PDCs used in the production of acetaldehyde (Pdc1, Pdc5 and acid (isobutyric acid) (corresponding alcohols isobutanol and Pdc6) have all been implicated in the production of the fusel isoamyl alcohol), compounds associated with foul, spoiled aro- aldehydes. Additionally, Aro10 is capable of this reaction, and mas. In some cases, metabolic engineering approaches have is primarily responsible for decarboxylating 2-phenylpyruvate been employed to actually increase production of these acids. to 2-phenylacetaldehyde (Vuralhan et al. 2003). Aro10 is also a Short branched-chain fatty acids such as 2-methylbutanoic acid, likely candidate for some variations in higher alcohol produc- isobutyric acid and isovaleric acid are valuable compounds in tion between species. Saccharomyces kudriavzevii produces more the food and pharmaceutical industries. The acids and their higher alcohols than S. uvarum or S. cerevisiae (Stribny et al. derivatives can be used as fragrances and flavorings (Yu et al. 2016). ScAro10 prefers phenylpyruvate but SkAro10 has a broader 2016). substrate preference, almost equally acting on phenylpyruvate, ketoisocoaproate, ketoisovalerate, ketomethylvalerate and even Environmental parameters and higher alcohol keto-γ -methylthiobutyrate (Stribny et al. 2016). Interestingly, the production interspecies hybrid, S. pastorianus, harbors three copies of the S. cerevisiae ARO10 gene and one copy from S. eubayanus. While The three-step process described above is situated amongst a both isozymes prefer phenylpyruvate as a substrate, SeuAro10 complex network of amino acid metabolism: there are multi- has much higher activity towards ketoisovalerate (Bolat et al. ple paths to each of the major alcohols that require significant 2013). Copy number variation and slight discrepancies in sub- regulation and balance during the fermentation process. Addi- strate preference add a level of aroma complexity to hybrid tionally, levels of each compound are dramatically affected by brewing yeasts. the medium composition, especially carbon source and nitrogen Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S108 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 5. Effect of environmental parameters on higher alcohol production. Effect on higher alcohol Parameter Condition production Reference Temperature Increase Increase Landaud et al. (2001) Oxygen Increase Increase Valero et al. (2002) Medium composition Csource Maltose Decrease (compared to sucrose, Younis and Stewart (1998) fructose, glucose) Sugar concentration Increase Decrease (not always) Younis and Stewart (1999) N source (total) Increase Decrease (co-regulation of LEU and Yoshimoto et al. (2002) BAT genes) NH Supplementation Decrease Vidal et al. (2013) Amino acids Supplementation Increase in respective higher Hernandez-Orte et al. (2005) alcohol (see Fig. 3) Vitamins Supplementation Increase Etschmann et al. (2004) Maillard compounds Increase Increase Dack et al. (2017) sources (Table 5). Since higher alcohols are mainly produced dur- 2016) but its overexpression causes an increase in production of ing active growth, factors that positively influence yeast growth higher alcohols (Kim, Cho and Hahn 2014). These conflicting re- simultaneously promote higher alcohol synthesis (Dekoninck sults could be due to a multitude of factors including differences 2012). If there is a surplus of exogenous amino acids, as shown in strain background or variations in media used for fermenta- by Ehrlich and others, production of these alcohols increases tions. Regardless, this points to a significantly more complicated (Ehrlich 1907;He et al. 2014). If amino acids are in short supply, relationship between the aminotransferases that may help con- the pathways will inevitably favor anabolic routes. This under- tribute to the diversity of higher alcohol production in different standing has been adopted by industry as a powerful way to di- strains. rect higher alcohol production (Etschmann et al. 2002;Vidal et al. As becomes apparent from the previous examples, sophisti- 2013; Lei et al. 2013a). cated metabolic engineering is needed to obtain highly produc- tive strains for higher alcohols. Several research teams focus on butanol isomers as these compounds can be used as alternative fuels. An exhaustive overview of metabolic engineering strate- Genetic factors and higher alcohol production gies for butanol isomer production has recently been published Engineered yeast strains for increased higher alcohol produc- elsewhere (Generoso et al. 2015). But, despite the extensive ef- tion are utilized both for increasing concentrations of the forts to improve the production yield of butanol isomers (and alcohols themselves and their respective esters. Overexpres- higher alcohols in general) in S. cerevisiae, the efficiency that can sion of ADH6 can increase isobutanol production (Kondo et al. be achieved by metabolic engineering is still significantly lower 2012) whereas overexpression of ADH1 can increase levels of compared to other hosts, such as Escherichia coli. Comparison 2-phenylethanol (Shen et al. 2016). Our understanding of the of central metabolism of metabolically engineered E. coli and S. ILV biosynthetic and Ehrlich pathways allows for complex, mul- cerevisiae revealed that flexibility of this metabolism is an im- tistep metabolic engineering to increase specific higher alco- portant factor in efficient production of butanols and propanols hols. For example, overexpression of ILV2, ILV3, and ILV5 in- (Matsuda et al. 2011). creases the flux towards isoleucine production (Fig. 3). If this is coupled with deletion of BAT1 (transaminase) and ALD6 (the aldehyde dehydrogenase) plus overexpression of ARO10 Physiological and ecological roles of higher alcohols and ADH2 (both alcohol dehydrogenases), the α-keto acid and aldehyde derivatives of isoleucine are pushed towards produc- Given the significant variation in higher alcohol production from tion of the higher alcohol (Fig. 4) (Park, Kim and Hahn 2014). different yeasts, it is perhaps not surprising that insects have Conversely, deletion of the alcohol dehydrogenase ADH with developed an ability to utilize these compounds as chemical overexpression of BAT1, ALD2 and ALD5 increases the produc- signatures. Many insect olfactory receptors are specifically at- tion of the fusel acids by diverting flux at the last Ehrlich tuned to the detection of higher alcohols and many of these step towards oxidation. These acids are also intermediates for compounds can elicit antennal and behavioral responses in in- production of value-added products in the chemical industry sects (Hallem and Carlson 2004; Saerens, Duong and Nevoigt (Yu et al. 2016). 2010; Knaden et al. 2012;Witzgall et al. 2012). It has been demon- Due to the complexity and intricate nature of these path- strated on several occasions that cultures of the yeast-like fun- ways, simple mutation does not always have the desired ef- gus Aureobasidium pullulans can lure a variety of insects, in- fect. For example, some studies show that deletion of ARO8 cluding hoverflies (Diptera: Syrphidae) (Davis and Landolt 2013) (one of the aromatic amino transferases) increases catabolism and social wasps (Vespula spp. (Hymenoptera: Vespidae) (Davis, of phenylalanine to its higher alcohol 2-phenylethanol (Romag- Boundy-Mills and Landolt 2012). In both cases, a synthetic blend noli et al. 2015;Shen et al. 2016) while others have demonstrated of higher alcohols, namely 2-methyl-1-butanol, isoamyl alco- that overexpression of the same gene also increases produc- hol and 2-phenylethanol, proved to be even more attractive to tion of higher alcohols (Yin et al. 2015;Wang et al. 2016b). Ad- the insects than the yeast culture. The wasps are known to ditionally, deletion of ARO9 has no apparent effect (Shen et al. act as vectors for A. pullulans, suggesting a strong interaction Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S109 between the wasps and the yeast species (Davis, Boundy-Mills whereas the longer hydrocarbon tails of fatty acid ethyl esters and Landolt 2012). reduce their capacity to diffuse across the membrane. There- Compound blends to mimic fermenting yeasts are com- fore, acetate esters impart significantly more influence over monly being implemented to combat agricultural pests. Many flavor and fragrance than the fatty acid counterparts. of the blends contain higher alcohols since these tend to assist Ester synthesis is carried out by alcohol-O-acetyl (or acyl)- in eliciting antennal responses and attraction. The beetle Car- transferases (AATases). In Saccharomyces cerevisiae, there are four pophilus humeralis infests and damages corn crops, and higher known enzymes: Atf1 and Atf2 are responsible for most acetate alcohol-containing blends are designed to mimic S. cerevisiae fer- ester production and Eeb1 and Eht1 synthesize the fatty acid menting corn and lure them (Nout and Bartelt 1998). The re- ethyl esters (SGD, Cherry et al. 2012). There is definitive evidence lated beetle, C. hemipterus, is similarly attracted to S. cerevisiae- that there are additional enzymes of both types in S. cerevisiae. produced higher alcohols, namely 2-pentanol, isoamyl alcohol, Double deletion of ATF1 and ATF2 results in complete loss of isobutanol and butanol (Phelan and Lin 1991). The weevil Arae- isoamyl acetate production but only a 50% reduction in ethyl ac- cerus fasciculatus (Coleoptera: Anthribide), a coffee bean pest, etate (Verstrepen et al. 2003c). Similarly, a double deletion of EEB1 was recently found to be attracted to 2-phentylethanol imply- and EHT1 does not eliminate fatty acid ethyl esters (Saerens et al. ing that the compound might serve as a potential lure (Yang et al. 2006). 2016). Recently, a third ethyl acetate-forming enzyme has been de- Higher alcohols can also serve as directory signals for insects. scribed (Kruis et al. 2017). The ethanol acetyltransferase 1 (Eat1) Fermentations of S. cerevisiae or a synthetic blend of five fer- was identified in Wickerhamomyces anomalus and defines a new mentation compounds, including ethanol, isoamyl alcohol and family of enzymes which is distinct from the canonical AATases. 2-phenylethanol, is sufficient to attract D. melanogaster (Becher Eat1 is actually a hydrolase that can perform thioesterase and et al. 2012). Among other compounds, higher alcohols produced esterase reactions in addition to formation of ethyl acetate. Ho- by Metschnikowia, including isoprenol, 2-phenylethanol and cit- mologs are found in several ethyl acetate-producing yeasts. Al- ronellol, can elicit antennal responses in the codling moth Cy- though a triple deletion has not yet been attempted, deletion of dia pomonella (Lepidoptera: Tortricidae) (Witzgall et al. 2012). The the S. cerevisiae Eat1 homolog, YGR015C, results in a 50% reduc- moths utilize the emitted aromas to orient themselves towards tion in ethyl acetate production, which complements the Atf1 suitable oviposition sites, such as yeast-infested apples that pro- and Atf2 production. vide a food source for larvae and protection from harmful fungal The enzymatic activities of these enzymes can differ sig- infestations. nificantly, even more so between different species and strains, Some higher alcohols have antifungal properties. Isoamyl al- adding to the variation of the final fermentation product. For cohol produced by Candida maltosa inhibits the germination of example, Atf1 has equal substrate specificity for isoamyl alco- filamentous fungi (Ando et al. 2012). Pichia anomala produces hol and 2-phenylethanol whereas Atf2 prefers isoamyl alcohol 2-phenylethanol potentially as a biocontrol agent against As- (Stribny et al. 2016). However, both Atf1 and Atf2 from S. kudri- pergillus a fl vus; the compound inhibits spore germination and avzevii or S. uvarum, have higher preference for 2-phenylethanol the production of the carcinogenic mycotoxin produced which compared to the S. cerevisiae homologs. This is directly re- can contaminate the crops P. anomala grows on (Hua et al. 2014). flected under fermentation conditions, where strains harboring Kloeckera apiculata likewise produces 2-phenylethanol to inhibit S. kudriavzevii and S. uvarum enzymes produce much more 2- growth of various Penicillium molds (Liu et al. 2014). Other stud- phenylethyl acetate. ies have also demonstrated anti-fungal effects of yeast volatiles from various species (several Candida species, S. cerevisiae, A. pul- Esters in industry lulans, Metschnikowia pulcherrima), but the specific effector com- pounds have not yet been identified (Fiori et al. 2014; Parafati et al. Esters are generally accepted as some of the most important 2015; Lemos Junior et al. 2016). contributors to the flavor and aroma of alcoholic beverages, Several higher alcohols such as 2-phenylethanol, tryptophol, imparting fruity and flowery notes to the product (Nordstr om ¨ tyrosol and farnesol can act as quorum-sensing molecules in di- 1966; Verstrepen et al. 2003a). During industrial fermentations, morphic yeasts, including S. cerevisiae, Debaryomyces hansenii and yeasts produce esters in very low concentrations, often only a Candida albicans. Secretion of the alcohols regulates the switch few parts per billion (ppb) (Lambrechts and Pretorius 2000). In- between unicellular yeast forms and filamentous forms (Chen cidentally, these natural concentrations hover around the fla- et al. 2004; Chen and Fink 2006; Gori et al. 2011). Moreover, it has vor threshold for humans and consequently, small changes in been speculated that these quorum-sensing molecules can play ester production can significantly alter perception of the prod- a role on the population level and influence the establishment of uct. There is a synergistic effect in the perception of many es- microbial communities in (semi-) spontaneous fermentations, ters, where a mixture of compounds will highlight or mask the such as wine, lambic beers and/or cheese, but evidence for such presence of others (Nordstrom ¨ 1964a; Suomalainen 1971). How- interactions is still lacking (Ciani and Comitini 2015). ever, an excess of esters often results in an unpalatable prod- uct, highlighting the importance of balance in the production of aroma compounds (Liu, Holland and Crow 2004). AMINO ACID METABOLITES: ESTERS The overall importance and complexity of ester production has led to considerable industrial research to optimize produc- Biochemistry of ester production tion. Interestingly, these compounds affect the quality of prac- Esters are formed by a condensation reaction between tically all food fermentations that involve yeasts, ranging from acetyl/acyl-CoA and an alcohol (Fig. 5). The use of acetyl- fermented beverages (Lilly, Lambrechts and Pretorius 2000;Ver- CoA or acyl-CoA divides esters into two different categories, strepen et al. 2003a), over bread (Birch et al. 2013; Aslankoohi et al. acetate esters and fatty acid ethyl esters, respectively. The small 2016), to chocolate (Meersman et al. 2016). Moreover, biotech- size and lipophilic nature of acetate esters allow them to readily nological production of high ester concentrations, especially diffuse from the cytoplasm into the extracellular medium ethyl acetate, has been studied for several years. Ethyl acetate Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S110 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 5. Ester synthesis in yeast. Left: general scheme of both types of ester production. Esters are the result of condensation reactions between an alcohol and an acetyl/acyl-CoA. (A) Acetate esters are produced through the actions of Atf1 and Atf2. (B) Fatty acid esters are produced by Eeb1 and Eht1. Right: examples of some of the most common esters discussed in this review. General aroma descriptors are listed in italics. is an environmentally friendly solvent with many industrial pression of ATF1 and BAT1 and subsequently alter ester levels applications but its production involves energy-intensive petro- (Saerens, Thevelein and Delvaux 2008). chemical processes. Several non-conventional yeasts, more In general, higher temperatures result in higher alcohol pro- specifically W. anomala, Candida utilis and especially duction and subsequent acetate ester production (Landaud, La- Kluyveromyces marxianus, all species with inherently high trille and Corrieu 2001) though this effect can vary given differ- ethyl acetate production, have been explored (Loser ¨ , Urit and ences in fermentation matrix, genetic background and the es- Bley 2014). ters of interest (Molina et al. 2007;Birch et al. 2013). Additionally, ATF1 and ATF2 expression are positively correlated with temper- ature and would result in increases in acetate ester production Environmental parameters and ester production (Saerens et al. 2008b). However, the volatile nature of acetate es- There are a multitude of parameters that can influence ester ters would lead to an overall decrease in concentration at exces- production in yeast which allows for significant modulation of sively high temperatures. This is the case in chocolate produc- the ester profile of foods or beverages without genetic manipu- tion; during post-fermentation processing, the chocolate mass lation (Table 6). However, given the complexity of the regulation is subjected to an hour-long mixing at temperatures as high as of enzyme and substrate availability, the exact outcome of mod- 75 C (Meersman et al. 2016). This production step results in the ifying one specific parameter is still hard to predict. In general, loss of many yeast-derived aroma compounds, including acetate acetate and ethyl ester production are often affected in the same esters. However, fatty acid esters, which dissolve more easily way by the same parameters (Saerens et al. 2008a). into the fat fraction of chocolate, are largely retained. The concentration and composition of fermentable carbon Dissolved oxygen and unsaturated fatty acids are negative sources as well as the carbon-to-nitrogen ratio have dramatic ef- regulators of ATF1 expression and, consequently, ester synthe- fects on ester production (Table 6) (Piddocke et al. 2009; Dekon- sis (Dufour, Malcorps and Silcock 2003). Interestingly, both com- inck et al. 2012). The direct connection to higher alcohols and pounds are shown to act on the same part of the ATF1 promo- their amino acid precursors makes ester production highly de- tor, namely the low-oxygen response element (Jiang et al. 2001). pendent on the nitrogen source. The concentration of free amino Therefore, oxygenation of the fermenting medium is a power- nitrogen (FAN), including amino acids and small peptides, pos- ful and straightforward tool to modulate ester production. How- itively correlates with acetate ester production (Procopio et al. ever, it is not always feasible to increase or decrease the oxygen 2013; Lei et al. 2013a, b). Increased nitrogen can also increase ex- content of the medium, as it can have undesirable side effects Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S111 Table 6. Effect of environmental parameters on ester production. Parameter Condition Effect on ester production Reference Temperature Increase Increase (not always) Molina et al. (2007), Saerens et al. (2008a) Oxygen Increase Decrease (decreased expression of Fujii et al. (1997), Anderson and Kirsop (1974) ester synthesis genes) Medium composition Unsaturated fatty acids Increase Decrease (decreased expression of Fujii et al. 1997, Anderson and Kirsop (1974) ester synthesis genes) Free amino nitrogen (FAN) Increase Increase (precursor availability Saerens et al. (2008a), Lei et al. (2013ba) and increased expression of ester synthesis genes) Sugar concentration Increase Increase (increased expression of Saerens et al. (2008b) ester synthesis genes) Csource Glucose, fructose, sucrose Increase (compared to maltose) Verstrepen et al. (2003b), Piddocke et al. (2009) Maillard compounds Increase Decrease Dack et al. (2017) Hydrostatic pressure Increase Decrease (increased dissoved CO ) Landaud et al. (2001), Meilgaard (2001) (e.g. irregular yeast growth, impaired flavor stability or increased isoamyl alcohol and isoamyl acetate (Oba et al. 2005). Similarly, risk of contamination). Adding unsaturated fatty acids can be growth with phenylalanine analogues (o-fluoro- and p-fluro- an interesting alternative without the undesired effects (Moon- DL-phenylalanine) selects for 2-phenylethyl acetate producers jai et al. 2002). (Fukuda et al. 1990, 1991). There have been interesting attempts Modifications to the fermentation vessel can alter the yeast to selectively enhance variations in either ATF1 or ATF2 given the cells’ microenvironment and affect physiological changes. A variations in which types of acetate esters are produced. Growth shift from small fermenters to tall, cylindroconical vessels in with farnesol analogs (1-farnesylpyridinium) favors Atf1 activity large breweries resulted large decreases in ester production (Hirooka et al. 2005), while supplementing medium with preg- (Meilgaard 2001). This was explained by the increased concen- nenolone favors Atf2 activity (Tsutsumi et al. 2002; Kitagaki and tration of dissolved carbon dioxide which inhibited overall de- Kitamoto 2013). In the latter example, the harmful steroid is me- carboxylation reactions, resulting in lower substrate levels for tabolized by Atf2 and therefore selects for strains with enhance- ester production (Landaud, Latrille and Corrieu 2001). ments of Atf2 activity. Those mutants would be able to increase levels of isoamyl acetate without affecting ethyl acetate. Experimental evolution utilizing lipid synthesis inhibitors has also resulted in strains with enhanced ester production. Se- Genetic factors and ester production lection on aureobasidin, a sphingolipid biosynthesis inhibitor, As acetate esters are quantitatively the most abundant group of resulted in mutations in MGA2 which has been implicated in esters in industrial fermentations, and are shown to have a ma- ATF1 regulation (Takahashi et al. 2017). Growth on cerlulin, a jor impact on flavor, it is not surprising that researchers have of- fatty acid synthesis inhibitor, selected for mutants of FAS2,a ten aimed to hijack the yeast’s ester production to diversify the fatty acid synthetase, with enhanced production of ethyl es- organoleptic characteristics of many diverse fermented foods. ters and the additional benefit of reduced acetic acid levels (see The total ester production and the relative proportions of each Fig. 5)(Ichikawa et al. 1991). A self-cloning sake strain equipped individual ester differs dramatically between species and strains with this mutation became the first genetically modified mi- (Steensels et al. 2014a; Padilla, Gil and Manzanares 2016). Thus, croorganism approved for industrial use in Japan (Aritomi et al. the most straightforward way to vary ester levels in fermenta- 2004). tion is to vary the yeast strain. Metabolic engineering to control ester formation has mostly targeted ATF1 and ATF2 expression or activity (Lilly, Lambrechts and Pretorius 2000; Hirosawa et al. Physiological and ecological roles of esters 2004; Lilly et al. 2006; Swiegers et al. 2006). Modulating expression of IAH1, an esterase, also affects ester concentrations (Lilly et al. The physiological role of ester production in yeast has been 2006; Zhang et al. 2012). Sexual hybridization has also been suc- under debate for several decades. It has been hypothesized cessfully applied to modulate ester production. Breeding meth- that ester synthesis helps to tune intracellular redox balance ods have helped increase and diversify ester production of com- (Malcorps and Dufour 1992) and that some esters help to mercial ale (Steensels et al. 2014a), lager (Mertens et al. 2015), maintain plasma membrane fluidity under stressful conditions sake (Yoshida et al. 1993; Kurose et al. 2000), wine (Bellon et al. (Mason and Dufour 2000). Additionally, esterification of toxic 2013) and even chocolate (Meersman et al. 2016). medium-chain fatty acids may facilitate their removal from cells Since formation of these compounds does not necessarily via diffusion through the plasma membrane (Nordstrom ¨ 1964b). impart a fitness advantage, there is no straightforward way While the intracellular roles are not quite understood, recently to select for desired ester production in experimental evolu- it has become clear that esters have significant roles extracellu- tion, mutagenesis or breedings set ups. Therefore, other ap- larly. proaches have been developed to select for enhanced esters. Of the many volatile compounds produced by yeast, esters Growth in the presence of a leucine analog (5,5 ,5 -trifluor-DL- represent one of the most important groups that can act as leucine) selects for variants with reduced positive feedback on insect semiochemicals, signaling the presence of rotting fruits leucine production which results in increased production of (El-Sayed et al. 2005). Fruity esters such as isoamyl acetate, ethyl Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S112 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 acetate and 2-phenylethyl acetate represent the core attractants which puts it in proximity to its potential host, D. melanogaster of various insects (Davis et al. 2013; Christiaens et al. 2014;Schei- (Dicke et al. 1984). dler et al. 2015). Deletion of ATF1 in S. cerevisiae significantly Similar to the higher alcohols, esters can have antifungal ef- reduces attraction of Drosophila melanogaster and simple re- fects, possibly to eliminate competition for the yeasts producing addition of isoamyl acetate or ethyl acetate can restore the flies’ them. Pichia anomala, P. kluyveri or Hanseniaspora uvarum all se- behavior (Christiaens et al. 2014). Isoamyl acetate is also respon- crete 2-phenylethyl acetate which can strongly inhibit growth sible for attraction of D. simulans, but the attraction is strongly and mycotoxin production by the fungus Aspergillus ochraceus dependent on the background chemical matrix (Gunther ¨ et al. (Masoud, Poll and Jakobsen 2005). 2015). There are also examples of possible species-specific re- sponses to various ester compounds. Drosophila suzukii has a AMINO ACID METABOLITES: SULFUR significantly higher response to isobutyl and isoamyl acetate, whereas D. melanogaster responds to ethyl hexanoate (Keesey, COMPOUNDS Knaden and Hansson 2015; Scheidler et al. 2015). The herbivo- The generic classification of ‘sulfur-containing’ opens a large rous drosophilid, Scaptomyza flava, a relative of D. melanogaster, and diverse array of compounds to consider including ev- has lost its ability to detect most yeast volatiles (Goldman- erything from basic thiols (such as hydrogen sulfide or Huertas et al. 2015). Genes encoding for neuronal receptors re- methanethiol) and sulfides (dimethyl sulfide, dimethyl disulfide, sponsible for detecting esters are either deleted or have loss etc.), thioethers and thioesters, sulfur-containing aldehydes and of function mutations in S. a fl va , demonstrating the important alcohols, as well as larger, polyfunctional thiols. Given the exten- connection between yeast volatiles and locating microbial food sive list of potential compounds, we focus on the assimilation of sources. sulfur, the connections to amino acid metabolism and industri- The black calla lily (Arum palaestinum) has taken advantage of ally relevant sulfur compounds. the drosophilids’ ability to detect esters. This plant has evolved to mimic yeast fermentation volatiles specifically by producing 2,3-butanediol acetate and acetoin acetate to lure drosophilids Biochemistry of sulfur assimilation and metabolism for pollination (Stokl ¨ et al. 2010). Recent evidence indicates that interactions within the D. All yeast-produced sulfur compounds arise during the melanogaster microbiome can alter behavior of the fly (Fischer catabolism or anabolism of the sulfur-containing amino et al. 2017). While the flies feed on yeasts, lactic and acetic acid acids methionine and cysteine. Since these amino acids are bacteria are major constituents of its gut microbiome. In fer- found at relatively low concentrations in both natural and menting fruits, all three microorganisms co-exist and the grow- industrial environments, yeasts are required to assimilate inor- ing microbes create a collaborative volatile profile which en- ganic sulfur via the sulfate reduction sequence (Fig. 6). Sulfates hances attraction of D. melanogaster. Acetate esters (isobutyl ac- are sequentially reduced to sulfide which can combine with etate, isoamyl acetate, 2-phenylethyl acetate, 2-methylbutyl ac- a nitrogen source (O-acetyl-serine or O-acetyl-homoserine) etate, methyl acetate, ethyl acetate) along with acetic acid and to form cysteine and subsequently, methionine. From this acetoin were determined as the key compounds in this interac- point, the amino acids can be incorporated into protein or tion (Fischer et al. 2017). re-metabolized to form other volatile sulfur compounds. In In combination with higher alcohols, esters can be attractive cases of low nitrogen, the amount of available O-acetyl-serine for agricultural pests such as the coffee bean weevil Araecerus or O-acetyl-homoserine is limited, and there is an overproduc- fasciculatus (Coleoptera: Anthribidae) and Carpophilus beetles as tion of sulfide. This is converted to hydrogen sulfide to allow they mimic volatiles of fermenting fruits (described in the pre- for diffusion out of the cell (Jiranek, Langridge and Henschke vious section) (Phelan and Lin 1991; Nout and Bartelt 1998;Yang 1995; Spiropoulos et al. 2000; Mendes-Ferreira, Mendes-Faia et al. 2016). Codling moths Cydia pomonella, a common apple pest, and Leao ˜ 2002; Swiegers and Pretorius 2005). Additionally, it utilizes esters and other aroma compounds emitted by Metch- has recently been shown that some sulfur compounds, such nikowia yeasts to locate suitable ovipositioning sites (Witzgall as ethanethiol, S-ethyl thioacetate and diethyl disulfide, can et al. 2012). be synthesized from excess H S, independent of methionine In addition to insects, the earthworm Eisenia fetida uses synthesis (Kinzurik et al. 2016). volatile cues, such as ethyl pentanoate and ethyl hexanoate, to From newly synthesized or exogenously added methionine navigate towards its food source Geotrichum candidum, a yeast- and cysteine, all other volatile sulfur compounds can be pro- like mold frequently used in the dairy industry (Zirbes et al. duced. Some of these pathways have not been fully mapped in 2011). Additionally, esters emitted by S. cerevisiae, such as methyl S. cerevisiae, but a general scheme can be drawn based on stud- acetate, ethyl acetate, propyl acetate, butyl acetate and amyl ies done on sulfur pathways in bacteria and other yeast species acetate, have strong attractive effects on nematode worms (Fig. 6). Bacteria have been more widely studied in regard to sul- (Balanova et al. 1979). fur production since the negative odors are generally associated Yeast-produced esters can also mediate host–parasite inter- with spoilage or desired aromas in specific types of cheese which actions. Honey bees produce isoamyl acetate-containing alarm utilize lactic acid bacteria (Kieronczyk et al. 2003). Tracing stud- pheromones that defend the hive against several predators and ies and genetic engineering attempts to manipulate levels of H S parasites. The beetle Aethina tumida (Coleoptera: Nitidulidae) is and the more desirable sulfur compounds have provided insight attracted to the isoamyl acetate. The beetles can vector the yeast into potential biosynthetic pathways (Arfi, Landaud and Bonn- Koamaea ohmeri to the hive which then begins to ferment and arme 2006; Cordente et al. 2012). produce more isoamyl acetate in high concentrations. This am- Cysteine and methionine breakdown has been linked to plifies the attraction of beetles and results in a vast infestation of dimethyl sulfide (DMS) production but it can also be formed beetles and larvae, causing enormous damage to the hive (Torto from the reduction of dimethyl sulfoxide (DMSO) by Mxr1 (me- et al. 2007). Similarly, the parasitic wasp Leptopilina heterotoma is thionine sulfoxide reductase) (Hansen 1999). For most other attracted to ethyl acetate (along with ethanol and acetaldehyde) sulfur-containing compounds, methanethiol is considered the Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S113 Figure 6. Sulfate reduction pathway leading to the production of sulfur-containing amino acids and compounds. (1) Extracellular sulfate is taken up through two transporters, Sul1 and Sul2, and sequentially reduced to sulfite and sulfide. (2) Excess sulfide can be converted to hydrogen sulfide which diffuses out o f the cell or (3) assimilated into amino acid synthesis pathways. (4) Production of α-ketobutyrate links this pathway to threonine and the branched amino acid synthesis pathways (Fig. 2). (5) Methionine can be acted on by a lyase to form methanethiol, which is a major precursor for numerous sulfur-containing aroma compounds. (6) Methanethiol can also be produced via transamination of methionine, which is also the first step of the Ehrlich pathway (Fig. 3). Adapted from Landaud (2008), Pereira et al.(2008), and Saccharomyces Genome Database (Cherry et al. 2012). primary precursor. Two different pathways lead to the produc- There is an important category of sulfur-containing com- tion of methanethiol: the lyase pathway or the transamina- pounds that are not directly synthesized by yeast. Polyfunctional tion pathway (Fig. 6, step 5). Demethiolation of methionine by thiols are present in the biomass used for fermentation but as a lyase is more comprehensively understood in bacteria but it non-volatile precursors. The cystathionine lyases Cys3, Irc7 and does occur in yeasts (Landaud, Helinck and Bonnarme 2008). Str3 release the polyfunctional thiols from the cysteine conju- The transamination pathway is essentially the Ehrlich pathway. gates (Tominaga et al. 1998;Howell et al. 2005; Holt et al. 2011; The intermediate keto-γ -methylthiobutyrate (also referred to as Roncoroni et al. 2011). 4-methylthio-2-oxobutyric acid or MOBA) can undergo a vari- ety of chemical and enzymatic reactions including conversion to Sulfur compounds in industry methanethiol. If MOBA continues via the Ehrlich pathway, there is subsequent production of methional, then methionol (via re- Sulfur compounds are most relevant in beer, wine and cheese- duction) or methylthio-propionic acid (via oxidation). Cysteine making industries. Unlike fusel alcohols or esters, some sulfur can also undergo conversion to the respective higher alcohol, compounds are classified as positive while others are considered 2-mercaptoethanol. Methanethiol can be produced through ox- negative odors. For example, the classic ‘rotten-egg’ odor usually idation or acylation reactions (Landaud, Helinck and Bonnarme associated with sulfur comes from hydrogen sulfide (H S) while 2008). furfurylthiol smells of roasted coffee. Other negative sulfur Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S114 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 7. Effect of environmental parameters on sulfur compound production. Effect on sulfur compound Parameter Condition production Reference Temperature Increase Increase (thiols) Howell et al. (2004), Masneuf-Pomarede et al. (2006) pH Decrease Decrease (H S, methanethiol, Bekker et al. (2016) DMS) Oxygen (fermentation) Increase Decrease (H S, methanethiol, Bekker et al. (2015) ethanethiol, methylthioacetate, ethylthioacetate, DMS) Oxygen (post-bottling) Increase Decrease (H S, methanethiol) Ugliano et al. (2012) Medium composition Copper sulfate Supplementation Decrease (H S and thiols; Kreitman et al. (2016) oxidation) N source (total) Increase Decrease (H S; dependent on Mendes-Ferreira et al. (2010), Spiropoulos et al. (2000) timing and methionine concentration) Botrytis cinerea infection Increase Increase (thiols) Thibon et al. (2010) compounds include methanethiol (cooked cabbage), sulfides Perhaps one of the most common problems in the wine in- (cabbage, cauliflower, garlic) and methylthioesters (cheesy, dustry is finding a balance between limiting production of the chives) (Cordente et al. 2012). Interestingly, the perception of undesirable H S while increasing levels of aroma-enhancing these compounds is highly context specific. While DMS typically volatile thiols. Complete wine fermentations are sometimes smells of cabbage, it can convey desired aroma notes to lager treated with copper sulfate, a process referred to as copper fin- beers and whiskey (Anness and Bamforth 1982; Hansen et al. ing, which effectively removes H S (Clark, Wilkes and Scollary 2002). Similarly, some of the sulfur-containing aromas are pro- 2015). However, the copper only requires presence of a free thiol duced by yeasts on the surface of soft cheeses and contribute to group to form a stable complex and will therefore also decrease their distinctive odor (Landaud, Helinck and Bonnarme 2008). levels of desirable thiol compounds. Furthermore, this strategy Some aroma-enhancing volatile thiols are produced by wine is ineffective in removing several sulfuric off-odors that lack a yeast from precursors present in grape must. Of interest are free thiol group, such as disulfides, thioacetates and cyclic sul- 4-mercapto-4-methylpentan-2-one (4MMP), 3-mercaptohexan- fur (Kreitman et al. 2016). 1-ol (3MH) and 3-mercaptohexyl acetate (3MHA), which impart Oxygenation both during fermentation or post-bottling can box tree (4MMP), passionfruit, grapefruit, gooseberry and guava also influence volatile sulfur compound profiles in wine. aromas (3MH and 3MHA) on the wine (Tominaga et al. 1998; Oxygen treatment during fermentation can reduce concentra- Dubourdieu et al. 2006). tions of H S, methanethiol and ethanethiol (Bekker et al. 2015). Sulfites can act as an antioxidant in wine and beer as well The effect of exposure after bottling is dependent on oxygen as protect against bacterial and Brettanomyces spoilage (Suzzi, ingress through the bottle cap or cork. More porous closures al- Romano and Zambonelli 1985; Divol, Toit and Duckitt 2012). low for some gas exchange and are correlated with lower H S However, sulfites produced by yeast are at relatively low lev- and methanethiol levels (Ugliano et al. 2012). DMS and DMDS els since they are reduced to be incorporated into amino acids. levels are unaffected; however, desirable volatile thiols are also Therefore, these are sometimes added prior to bottling to help reduced and are thus better conserved in air-tight conditions stabilize the final product. compared to oxygen permeable conditions (Lopes et al. 2009). Genetic factors and sulfur compound production Environmental parameters and sulfur compound Sulfur compound production widely varies between S. cerevisiae production strains and other species. Genetic engineering strategies have Since several sulfur compounds are considered to negatively targeted several of the genes associated with sulfur assimila- affect product quality, several strategies have been developed tion (Fig. 6). Mutation of MET5 or MET10 blocks the conversion to reduce their emission (Table 7). Low nitrogen conditions in- of sulfite to sulfide and reduces H S production (Sutherland crease the yeast cell’s need for amino acids which would in- et al. 2003; Cordente et al. 2009; Linderholm et al. 2010; Bisson, crease general sulfur assimilation. This leads to increased pro- Linderholm and Dietzel 2013). Overexpression of the cystathio- duction of H S so it has been common practice for decades to nine synthetase CYS4 also reduces H S production by driving 2 2 add nitrogen sources to fermentation medium (Jiranek, Lan- the sulfide towards amino acid synthesis (Tezuka et al. 1992). gridge and Henschke 1995; Mendes-Ferreira, Mendes-Faia and Mutating MET14 limits sulfur assimilation overall (Donalies and Leao ˜ 2004). However, this effect is dependent on the timing of Stahl 2002). Additionally, mutations in MET2 (produces O-acetyl- supplementation, yeast strain and the presence of methionine homoserine) or SKP2 (a potential regulator of sulfur assimilation (Spiropoulos et al. 2000; Mendes-Ferreira et al. 2010;Barbosa, genes) increase levels of sulfite and H S (Hansen and Kielland- Mendes-Faia and Mendes-Ferreira 2012). The strongest decrease Brandt 1996; Yoshida et al. 2011). DMS levels can be reduced by in H S levels is obtained when nitrogen source is added concur- disrupting MXR1, which prevents the conversion of DMSO to rently with methionine. DMS (Hansen et al. 2002). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S115 Table 8. Effect of environmental parameters on phenolic compound production. Effect on phenolic compound Parameter Condition production Reference Brettanomyces Medium composition Antimicrobial agents (sulfite, chitosans, ...) Supplementation Decrease (inhibits growth) Portugal et al. (2014) Weak acids and sorbic acid Supplementation Decrease (inhibits growth) Wedral et al. (2010) Low electric current Application of ∼200 mA Decrease (inhibits growth) Zuehlke et al. (2013) Pulsed electric field Application of ∼30 kV/cm, Decrease (inhibits growth) Zuehlke et al. (2013) 1–4 μs pulses Saccharomyces Temperature Increase Increase Vanbeneden (2007), Cui et al. (2015) Medium composition Csource Glucose Increase (compared to fructose, Vanbeneden (2007) maltose, sucrose, galactose) Csource Fructose, maltose, sucrose Increase (compared to galactose); Vanbeneden (2007) decrease (compared to glucose) Csource Galactose Decrease (compared to glucose, Vanbeneden (2007) fructose, maltose, sucrose) Top pressure Increase Decrease (increase in dissolved CO)Vanbeneden(2007) Fermentation practice Top cropping Decrease (less yeast sedimentation) Vanbeneden (2007) Enhanced release of aromatic thiols from biomass precur- which are trained by humans to locate underground truffles sors can be achieved by variations in the lyases, specifically the (Talou et al. 1990). β-lyases IRC7 and STR3.Many S. cervisiae strains have 38 bp dele- tion in the IRC7 gene, resulting in low levels of 4MMP. Strain PHENOLIC COMPOUNDS selection for β-lyase activity or overexpressing STR3 or a full- length copy of IRC7 greatly enhances 4MMP and 3MH release Biochemistry of phenolic compound production (Holt et al. 2011; Roncoroni et al. 2011;Belda et al. 2016). Pre-treatment of various lignin polymers of plant cell walls is a common practice in the fuel and beverage industries. The bioprocessing of these polymers prior to the fermentation pro- Physiological and ecological roles of sulfur compounds cess releases a variety of furans, carboxylic acids and phenolic compounds which can greatly inhibit microbial growth (Klinke, Hydrogen sulfide plays an important role in the physiology of Thomsen and Ahring 2004). Many microbial species, such as yeast cells. As described above in the acetaldehyde section, yeast Saccharomyces cerevisiae, Aspergillus niger, Pseudomonas aeruginosa cells exhibit glycolytic oscillations, in which they coordinate and Escherichia coli, counteract the negative impact by convert- their metabolism. Hydrogen sulfide can also cause respiration ing these compounds into less toxic molecules. For example, inhibition and therefore plays a role in regulating respiratory os- vanillin, a phenolic guaiacol, can be detoxified by conversion to cillations (Sohn, Murray and Kuriyama 2000; Lloyd and Murray vanillyl alcohol by yeast Adh6 (Wang et al. 2016a). Several of the 2006). hydroxycinnamic acids, such as cinnamic acid (phenylacrylic Methionol has been shown to activate an olfactory response acid), caffeic acid, ferulic acid and p-coumaric acid, can be decar- neuron in D. melanogaster (de Bruyne, Foster and Carlson 2001) boxylated to less toxic phenolic compounds which have a large and attract the fruit flies (Farhadian et al. 2012; Knaden et al. 2012) impact on industrial fermentations (Fig. 6). but concentrations used in those studies were higher than what In S. cerevisiae, there are two enzymes essential for decar- is typically produced by fermenting yeasts. However, it has been boxylation of the hydroxycinnamic acids encoded by PAD1 and shown that natural levels of methionol from vinegar and wine FDC1 (phenylacrylic acid decarboxylase and ferulic acid decar- elicit an antennal response from D. suzukii and when mixed with boxylase). For several years, it was unclear how the genes inter- other compounds (acetic acid, acetoin and ethanol) it effectively acted to produce phenolic compounds. In some studies, PAD1 attracts the flies (Cha et al. 2014). This indicates that methionol was assumed to be the sole responsible enzyme for this reac- could play a relevant ecological role in yeast–drosophilid com- tion as deletion or mutation resulted in complete loss of activity munication. but it was clearly demonstrated that both PAD1 and FDC1 are re- Truffles host various yeast and bacteria and while the pro- quired for the decarboxylation of hydroxycinnamic acids (Mukai duction of volatile compounds overlaps between the species, it et al. 2010). It has now been shown that PAD1 possesses no de- has been speculated that yeasts contribute to the truffle aroma, carboxylase activity but instead is responsible for formation of largely defined by sulfuric compounds such as DMS, DMTS and a modified flavin mononucleotide (FMN) which is required for 3-(methylsulfanyl)-propanal (Buzzini et al. 2005; Vahdatzadeh, FDC1 decarboxylase activity (Lin et al. 2015a;Payne et al. 2015; Deveau and Splivallo 2015). DMS is one of the defining cues for White et al. 2015). pigs, which use truffles as a food source, as well as for dogs, Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S116 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 7. Production of phenolic compounds. Hydroxycinnamic acids are released during pre-processing of biomass. Yeast cells can decarboxylate these toxic com- pounds to less harmful forms through the actions of Fdc1. Fdc1 requires a cofactor FMN which is produced by Pad1. The compounds are then secreted and can be further reduced by a vinylphenol reductase, typically by contaminating yeast or bacterial species. Phenolic compounds in industry on the precursor availability in the fermentation medium. In- creased precursor concentrations not only increase substrate During fermentation, the actions of Pad1 and Fdc1 convert fer- availability but also activate transcription of PAD1 and FDC1 ulic acid, p-coumaric and caffeic acid to 4-vinylguaiacol (4-VG), (Vanbeneden 2007). Other fermentation parameters, such as 4-vinylphenol (4-VP) and 4-vinylcatechol (4-VC), respectively temperature and carbon source, have been shown to affect for- (Fig. 7). Subsequently, these compounds can be reduced to form mation of phenolic compounds, but the underlying mechanisms 4-ethylguaiacol (4-EG), 4-ethylphenol (4-EP) and 4-ethylcatechol are not understood (Vanbeneden 2007;Cui et al. 2015). (4-VC) by vinylphenol reductase (Vanderhaegen et al. 2003;Van- beneden, Delvaux and Delvaux 2006; Hixson et al. 2012). Both 4-VG and 4-EG are associated with more pleasant clove-like or Genetic factors and phenolic compound production spicy aromas, while 4-VP and 4-EP aromas are considered more medicinal and ‘Band-Aid’-like. As Saccharomyces generally lacks Surprisingly few attempts have been performed to modify phe- reductase activity, 4-EG, 4-EP production during fermentation nolic compound production in industrial strains. This is due is an indicator of the presence of Brettanomyces (Steensels et al. in part to the simplicity of their production and the fact that 2015). These phenolic compounds are significant contributors to many industrial yeasts have already acquired natural mutations fermentation aromas but their role is ambiguous. In certain spe- to block phenolic compound production. It has recently been es- cialty beer styles, such as wheat, Hefeweizen, Lambic, American tablished that selection for PAD1 and FDC1 loss-of-function mu- coolship ale and acidic ale beer, the phenolic flavors are desired tants is one of the key drivers in the domestication of industrial and help define the style. However, the same compounds are S. cerevisiae lineages associated with beer and sake production perceived negatively in most other fermented beverages and are (Gallone et al. 2016; Gonc¸alves et al. 2016). This selection is not commonly referred to as ‘phenolic off-flavors’ (POF) (Vanbene- observed in baking or bioethanol strains as in these cases, phe- den 2007). nolic compounds are likely less detrimental, either because the flavor disappears during baking or the product is not destined for consumption. Additionally, for strains used in beer styles Environmental parameters and phenolic compound where phenolic compounds are desired, selection for mutations in these genes is not observed. production Given the general association as ‘off-flavors’, several aspects of the fermentation process have been modified to reduce pheno- Physiological and ecological roles of phenolic lic compound production (Table 8). The undesired presence of compounds Brettanomyces during fermentation can be attenuated by various inhibitors (e.g. sulfites or chitosans) or electric currents. Produc- The POF-negative character of many industrial yeasts is espe- tion of phenolic compounds by Saccharomyces heavily depends cially striking since the phenotype is preserved in all wild strains Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S117 Figure 8. Summary of the ecological roles of aroma compounds. This review has summarized a variety of physiological and ecological roles of yeast aroma compounds. This figure depicts some of the major organisms described to illustrate the vast number of compounds that they interact with. Positive ( +) indicates a generally positive interaction such as attraction, increased growth or behavior. Negative (–) indicates a negative interaction such as inhibited growth or repulsion. that have currently been analyzed, which indicates a strong fit- Low oxygen enhances activity of the vinylphenol reductase ness advantage of these genes in natural environments (Gallone (Fig. 7) and subsequently reduces levels of its cofactor, NADH et al. 2016). Since hydroxycinnamic acids are antimicrobial com- (Curtin et al. 2013). pounds, the ability of some yeasts to convert these acids to less Drosophila melanogaster uses volatile ethyl phenols as indica- harmful phenolic compounds provide them with resistance and tors for the presence of hydroxycinnamic acids which are potent promotes growth (Baranowski et al. 1980; Larsson, Nilvebrant dietary antioxidants. Since the insects do not possess the ability ¨ ¨ and Jonsson 2001; Richard, Viljanen and Penttila 2015). Addition- to detect the acids directly, they have developed specialized ol- ally, formation of the ethyl derivatives could play a role in main- factory neurons for detecting the ethyl phenols instead (Dweck taining redox balance in the cell in oxygen-limited conditions. et al. 2015). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S118 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 CONCLUSION et al. 2015). Though we know quite a lot about individual aroma compounds, the complex interactions between them are rela- Humans realized the potential of fermentation several thousand tively understudied. Additionally, it is likely that there are more years ago, and have since been exploiting the natural versatility aroma compounds to be identified, especially in an ecological of yeast aroma production. Fermented foods and beverages pro- context. Moreover, it is yet unclear if the insect and animal re- vide several advantages including longer shelf lives and a pleas- cipients perceive the compounds discretely or as a blend. Such ing euphoric effect. Over time, the procedures for fermentations interactions could also be interesting from a human perspective became more sophisticated and more refined. Eventually, other especially in the case of bioremediation in agriculture, where uses for fermentation became apparent and the use of yeast for microbial-produced compounds can be exploited as insect re- industrial purposes sparked a whole new field of research and pellants or attractants. The plethora of already observed inter- development. There is now genetic evidence that demonstrates actions that are influenced by aroma compounds illustrates that how much humans have driven the evolution of industrial yeast aroma-producing microbes may play important, yet underesti- species to select for desired aroma traits (Gallone et al. 2016, mated roles in the ecosystem. Gonc¸alves et al. 2016). Moreover, in the past few decades, new technologies have significantly advanced and refined the selec- tion process (Steensels et al. 2014b). We now utilize specific yeast ACKNOWLEDGEMENTS strains to produce biofuels, pharmaceutical compounds, flavors The authors would like to thank all Verstrepen laboratory mem- and fragrant additives. bers, especially Karin Voordeckers, for their help and sugges- Selection for specific aromas has also been observed in nat- tions. ural strains (Gallone et al. 2016) but in some cases, wild yeasts maintain some aromas that humans have deemed undesirable. There are also species-specific enhancements of various aroma FUNDING compounds through small variations in the biosynthetic genes. The authors also acknowledge funding from the Belgian This leads to questions about what possible physiological roles American Education Foundation (MCD), KU Leuven (RP and the different aroma compounds may have and whether there JS). KJV also acknowledges funding from an ERC Consolida- are fitness advantages to produce them. tor Grant CoG682009, HFSP program grant RGP0050/2013, KU Microbial aroma compound production is important in both Leuven NATAR Program Financing, VIB, EMBO YIP program, industrial and ecological settings. Aroma compounds very of- FWO, and VLAIO. ten signal desirability or identify potentially harmful conditions. In many cases, the physiological role of aroma formation re- Conflict of interest. None declared. mains unknown, but several hypotheses have been proposed. Some aromas are simply by-products of detoxification of other- wise harmful compounds, such as the conversion of hydroxycin- REFERENCES namic acids and esterification of toxic medium chain fatty acids Adams MR, Moss MO. Food Microbiology. Cambridge, UK: Royal (Nordstrom ¨ 1964b, Klinke, Thomsen and Ahring 2004). 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Publisher: Oxford University Press
Copyright: Copyright © 2022 Federation of European Microbiological Societies
ISSN: 0168-6445
eISSN: 1574-6976
DOI: 10.1093/femsre/fux031
pmid: 28830094
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Abstract

Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 FEMS Microbiology Reviews, fux031, 41, 2017, S95–S128 doi: 10.1093/femsre/fux031 Review Article REVIEW ARTICLE Physiology, ecology and industrial applications of aroma formation in yeast 1,2 1,2 1,2 3 Maria C. Dzialo , Rahel Park , Jan Steensels , Bart Lievens 1,2,∗ and Kevin J. Verstrepen Laboratory for Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Gaston Geenslaan 1, B-3001 Leuven, Belgium, Laboratory for Systems Biology, VIB Center for Microbiology, Bio-Incubator, Gaston Geenslaan 1, 3001 Leuven, Belgium and Laboratory for Process Microbial Ecology and Bioinspirational Management (PME&BIM), Department of Microbial and Molecular Systems, KU Leuven, Campus De Nayer, Fortsesteenweg 30A B-2860 Sint-Katelijne Waver, Belgium Corresponding author: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, VIB Center for Microbiology, Bio-Incubator, Gaston Geenslaan 1, B-3001 Leuven, Belgium. Tel: +32 (0)16 75 1390; E-mail: kevin.verstrepen@kuleuven.vib.be One sentence summary: This review explores the biochemical pathways leading to production of a wide array of aroma compounds, the various industrial applications that have been developed around use of aroma compounds, as well as the newly uncovered physiological and ecological roles the various compounds may play. Editor: Eddy Smid ABSTRACT Yeast cells are often employed in industrial fermentation processes for their ability to efficiently convert relatively high concentrations of sugars into ethanol and carbon dioxide. Additionally, fermenting yeast cells produce a wide range of other compounds, including various higher alcohols, carbonyl compounds, phenolic compounds, fatty acid derivatives and sulfur compounds. Interestingly, many of these secondary metabolites are volatile and have pungent aromas that are often vital for product quality. In this review, we summarize the different biochemical pathways underlying aroma production in yeast as well as the relevance of these compounds for industrial applications and the factors that influence their production during fermentation. Additionally, we discuss the different physiological and ecological roles of aroma-active metabolites, including recent findings that point at their role as signaling molecules and attractants for insect vectors. INTRODUCTION 1996), and capping off with an in-depth look at the phenotypic and genetic diversity of nearly 200 industrial yeasts last year, When presented with the appropriate nutrients, yeasts pro- including a detailed profiling of differences in aroma formation duce complex bouquets of aroma compounds including esters, (Gallone et al. 2016; Gonc¸alves et al. 2016). Interestingly, these re- higher alcohols, carbonyls, fatty acid derivatives and sulfur com- cent studies demonstrate that humans have helped drive the pounds. Moreover, while not directly synthesized by yeasts, domestication of yeasts, at least partly based on their ability to volatile thiols and monoterpenes are sometimes released from selectively produce desired aromas and reduce unwanted com- odorless precursors by yeast-derived enzymes (Tominaga et al. pounds. 1998;Moreira et al. 2005). Our understanding of the fermenta- Given its importance in product quality, much effort has been tion process and the associated aroma production by yeast has devoted to fine-tune flavor production by yeast in an indus- increased exponentially over the last centuries, from the discov- trial setting. Globally, two approaches can be applied to steer ery of yeast cells in 1680, to the sequencing of the entire Saccha- the yeast’s physiology to alter aroma production: adjusting the romyces cerevisiae genome just two decades ago (Goffeau et al. Received: 17 February 2017; Accepted: 6 June 2017 FEMS 2017. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. S95 Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S96 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 1. Overview of aroma compound production. This review covers a large array of aroma compounds produced during yeast fermentation. The basic fermentation of pyruvate (green/red) leads to several carbon-based compounds, including ethanol and carbon dioxide. Pyruvate also feeds into the anabolism of amino acids, leading to production of vicinal diketones (pink). Metabolism of amino acids is responsible for numerous aroma compounds including higher alcohols and esters (purple) as well as sulfur-containing compounds (blue). Additionally, the phenolic compounds are derived from molecules found in the media (orange). Compoundsshown in darker shades are considered intermediates while lighter shades are aroma compounds discussed in this review. Dotted lines indicate import/export of compounds, solid lines represent biochemical reactions (not indicative of number of reactions). fermentation environment or modifying the genotype of the In this review, we provide an overview of the current under- production strain. Adjusting the environmental parameters standing of aroma production in yeasts in an industrial, phys- can be a convenient, often very powerful, way to optimize iological and ecological context. We attempt to provide a more production without complex biotechnological procedures nor global review covering major compounds discussed commonly a thorough understanding of basic yeast physiology. How- in industry and ecology (Fig. 1). For each metabolite category, ever, given the recent expansion of the available yeast bio- we first illustrate the biochemical pathways which are crucial diversity, strategies to modify yeasts and the genetic toolbox for understanding the rationale behind much of the industrial to genetically engineer strains, biotechnologists can now se- research. Note that much of the biochemical review in this pa- lect or develop new yeasts with aromatic properties far be- per will refer to Saccharomyces cerevisiae since research into the yond what is achievable through adjustment of environmental specific mechanisms of the fermentation process is commonly parameters. based on this species, given its central role as a model organism While humans have been advancing, and refining the ex- and as a robust fermenter in industry. We then discuss the in- ploitation of yeast aroma for several millennia, it remained un- dustrial roles of the aroma compounds that humans have devel- known why yeast cells produce these flavor-active molecules oped. We also highlight key environmental parameters, such as in the first place. Over the past decades, several hypotheses temperature and medium composition, that are commonly ad- for possible physiological roles have been proposed, includ- justed to affect specific compound production as well as some ing synthesis of specific cellular building blocks, redox balanc- modifications to genetic background that have been developed ing and detoxification reactions, but the evidence for these re- to influence aroma production. Lastly, we explore some of the mained very limited. Recent studies, however, have begun to possible physiological and ecological roles of these aroma com- uncover a fundamental and central role of aroma production pounds. in the lifestyle of yeast. Specifically, it has been shown that yeast-derived volatiles can have integral roles in natural envi- ronments, ranging from signaling information to animal vec- PRIMARY FERMENTATION METABOLITES: tors, regulation of fungal growth and communication between ETHANOL yeast cells or colonies (Richard et al. 1996; Bruce et al. 2005; In many industrial fermentation processes, ethanol is the most Leroy et al. 2011;Davis et al. 2013). The interaction between important compound produced by yeast. Moreover, it is the pro- yeasts and insects has been studied intensively the past decade duction of this primary metabolite that originally sparked inter- and there is increasing evidence that attraction of many in- est for the fermentation of beverages. Early civilizations devel- sect species to fermenting fruits is mediated by the volatiles oped fermentation methods to exploit the benefits of ethanol; emitted by the yeasts rather than by the fruit itself (Becher ethanol prolongs shelf-life, improves digestibility and acts as et al. 2012). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S97 Figure 2. Production of ethanol, acetaldehyde, acetic acid, and CO . Fermentable carbons are assimilated from the medium and converted to glycerol or pyruvate via glycolysis. Pyruvate can be shuttled towards the TCA cycle and respiration (left) or towards alcoholic fermentation (right). For some conversions, multiple enzymes can perform the reaction and are indicated on the figure. Note: Ald4, Ald5 and Adh3 are mitochondrial enzymes but perform the same reactions as the other cytosolic ALD and ADH enzymes. a euphoriant (Alba-Lois and Segal-Kischinevzky 2010). Today, fermentation and respiration. In direct competition with pyru- ethanol still forms the basis of many fermented products, ei- vate dehydrogenase, PDCs can remove excess pyruvate from the ther destined for consumption or for renewable energy. More- pathway and divert it towards ethanol production. over, ethanol is a volatile aroma compound, although its sen- Acetaldehyde is subsequently converted into ethanol by an sorial properties are perhaps less pronounced than some of the alcohol dehydrogenase (ADH). This type of oxidoreductase can more flavorful molecules that are also formed as byproducts of catalyze the reversible interconversion of alcohols and the cor- the fermentation pathway. responding aldehydes or ketones. The wide array of substrates available for ADHs throughout the metabolic pathways requires substantial regulation to ensure a balance of the desired prod- Biochemistry of ethanol production ucts and intermediates. It is therefore not surprising that eu- karyotes, even humans, have numerous ADH enzymes. Even a Although yeasts have been utilized for their fermentative capac- simple eukaryote like S. cerevisiae has seven ADH genes as well ity for millennia, the molecular components of this basic path- as several aryl-alcohol dehydrogenases (AAD). Adh1 is the pri- way were only discovered in the last few decades (Bennetzen mary enzyme for producing ethanol during fermentation and for and Hall 1982; Schmitt, Ciriacy and Zimmermann 1983). + replenishing the pool of NAD , while Adh2 is glucose repress- Central metabolism begins with the basic conversion of sug- ible and will oxidize ethanol as a carbon source when needed ars into pyruvate, yielding energy in the form of ATP and reduced (Leskovac, Trivic´ and Pericin 2002). Adh3 is constitutively ex- NADH cofactors. The divergence of pyruvate after glycolysis is pressed during both ethanol production and utilization but as an essential regulatory point in metabolism, which has made it it is expressed in the mitochondria, its primary role is likely to a hotspot for biochemical and industrial research. There are two maintain redox balance (Bakker et al. 2001; de Smidt, du Preez basic directions pyruvate can take at this point: fermentation or and Albertyn 2012). respiration. In most eukaryotes, this is dependent on the pres- ence of oxygen. In aerobic conditions, pyruvate will be converted to acetyl-coA by actions of a pyruvate dehydrogenase and head Ethanol in industry towards the citric acid cycle (Fig. 2). Under fermentative (anaer- obic) conditions, pyruvate is diverted towards fermentation. Ethanol is an important yeast metabolite for most products in- Conversion of pyruvate to ethanol is a two-step process. First, volving yeast fermentation. It is a vital ingredient of fermented pyruvate is converted to acetaldehyde by a pyruvate decarboxy- beverages and is used as a prominent renewable biofuel but lase (PDC), releasing carbon dioxide as waste. There are three ethanol also plays a role in product quality of other fermented confirmed PDC enzymes encoded in the Saccharomyces cerevisiae products where the connection is perhaps more obscure. For genome (Saccharomyces Genome Database; Cherry et al. 2012). example, during baking, ethanol produced by yeast has a These enzymes act as a key metabolic branch point between strong impact on dough extensibility and gluten agglomeration Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S98 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 1. Effect of environmental parameters on ethanol production. Effect on ethanol Parameter Condition production Reference Temperature Above optimal Decrease (lower ethanol Coleman et al. (2007) tolerance) pH Increase Increase (increased Lam et al. (2014) proton electrochemical gradient) Oxygen Increase Increase (higher cell Alfenore et al. (2004) viability) Medium composition Csource Preferred sugars Decrease (undesired Verstrepen et al. (2004) (glucose, sucrose) side effects on physiology) Nsource NH , glutamate Decrease (compared to Albers et al. (1996) amino acids) Metal ions Supplementation Increase Tosun and Ergun (2007) Vitamins Supplementation Increase Alfenore et al. (2002) Lipids (fatty acids, sterols) Supplementation Increase Pham et al. (2010) Nutrient-rich mixtures Supplementation Increase Jones and Ingledew (1994) Potassium Supplementation Increase (increased Lam et al. (2014) potassium membrane gradient) Electric field Application of 15V Increase (alternative Mathew et al. (2015) source of redox power) Enzyme (Amylase) Supplementation Increase (more available Nigam and Singh (1995) sugars) (Jayaram et al. 2014). During cocoa fermentations, the ethanol and oxidizing power (Schievano et al. 2016). Application of a produced by yeast serves as a carbon source for acetic acid bac- static potential of up to 15 V (without any resulting current) to a teria (which are vital for cocoa flavor) and triggers biochemical S. cerevisiae culture resulted in a 2-fold yield of ethanol (reaching reactions within the cocoa bean that lead to the production of 14% v/v) and 2 to 3-fold faster fermentation rate (Mathew et al. various aromas and aroma precursors (Hansen, del Olmo and 2015). In another strategy, Lam et al. (2014) strengthened the op- Burri 1998). posing potassium and proton electrochemical membrane gradi- Given the central role of ethanol in alcoholic fermentation ents during fermentations, which led to an enhanced resistance processes, much research has focused on improving speed and to multiple alcohols, including ethanol (Lam et al. 2014). efficiency of alcohol production by yeasts over the past few decades, especially in the bioethanol industry. Interestingly, there is also an emerging trend towards fermented beverages Genetic factors and ethanol production with reduced ethanol content (Wilkinson and Jiranck 2013;WHO 2014). This is driven by the increasing demand from both con- One of the easiest ways to obtain yeasts with modulated ethanol sumers and producers to reduce problems associated with high production capacity is screening the available natural biodiver- alcohol levels. Too much ethanol can compromise quality of the sity. Most fermentation processes are conducted with S. cere- product and excessive alcohol intake is associated with various visiae, or very related species, such as S. pastorianus (lager beer) health issues. From a financial standpoint, high alcohol content or S. bayanus (some wines). It has been shown numerous times can increase the costs to the consumer in countries where taxes that traits such as ethanol tolerance or ethanol accumulation are calculated based on ethanol content. capacity are strain dependent within S. cerevisiae (Swinnen et al. 2012;Snoek et al. 2015; Gallone et al. 2016) and nature of- ten harbors superior variants. For example, Brazilian bioethanol Environmental parameters and ethanol production plants initially inoculated with baker’s yeasts but were rapidly Modifying the fermentation parameters, including carbon taken over by wild autochthonous strains (Basso et al. 2008). sources, trace elements and even temperature, has proven to be These wild contaminants have been used as commercial starter effective measures for altering ethanol production by industrial cultures ever since. Moreover, while Saccharomyces spp. are still yeasts (Table 1). the preferred organism for most fermentation processes, alter- However, the positive effects of these medium adjustments native species such as Brettanomyces bruxellensis, Metschnikowia are often strain dependent (Remize, Sablayrolles and Dequin pulcherrima, Torulaspora delbrueckii, Saccharomycodes ludwigii and 2000), and in case of food production, the potentially disadvan- Zygosaccharomyces rouxii produce increased (Passoth, Blomqvist tageous side effect on aroma must be assessed carefully. Other, and Schnur ¨ er 2007; Steensels and Verstrepen 2014; Radecka et al. more adventurous, strategies have been recently described. For 2015) or decreased (Contreras et al. 2015;DeFrancesco et al. 2015; example, ‘electro-fermentation’ imposes an electrical field on Morales et al. 2015; Canonico et al. 2016) levels of ethanol, thereby the fermentation to serve as an alternative source of reducing further expanding the portfolio of potential industrial yeasts. Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S99 Nevertheless, numerous research projects have aimed to expression of a non-phosphorylating, NADP -dependent GAP modify ethanol production, or fermentation efficiency in gen- reduces formation of cytosolic NADH and results in decreased eral, within a specific strain by altering the genetic back- glycerol with increased ethanol (Bro et al. 2006). ground. However, the large number of enzymes and branch Lastly, total ethanol accumulation can be improved. This trait points involved can complicate the results of adjusting is related to ethanol tolerance, but different molecular mech- genes and metabolites involved in central carbon metabolism. anisms can underlie them (Pais et al. 2013). Reverse metabolic Ethanol production of industrial strains has been adjusted engineering identified three natural alleles that can improve by various strategies, including increased ethanol tolerance ethanol accumulation capacity in yeast: ADE1 (a nucleotide syn- (Zhao and Bai 2009; Lam et al. 2014;Snoek et al. 2015; thase), URA3 (a decarboxylase involved in pyrimidine synthesis) Voordeckers et al. 2015;Ohta et al. 2016), reduced production of and KIN3 (kinase involved in ethanol tolerance) (Pais et al. 2013). alternative metabolites (e.g. glycerol) (Remize, Sablayrolles and In another study, large-scale, robot-assisted genome shuffling Dequin 2000; Pagliardini et al. 2013; Hubmann et al. 2013a)and yielded hybrids with an increased ethanol accumulation of up to increased ethanol accumulation capacity (Pais et al. 2013;Snoek 7% relative to a widely applied bioethanol strain (Ethanol Red), et al. 2015). but the underlying genetic factors were not identified (Snoek During many industrial fermentation processes, especially et al. 2015). in bioethanol fermentations or high-gravity brewing, yeast en- Some studies aim to reduce ethanol production to fit grow- counter extremely high ethanol concentrations, sometimes ing trends of low alcohol beverages. The main challenge is to reaching up to 20%–25% v/v. This can quickly become toxic achieve the ethanol reduction without the loss of product qual- to the cells and has thus led to considerable efforts in in- ity, as ethanol production is often tightly linked to production creasing ethanol tolerance of industrial yeast strains. There- of other volatile metabolites. Methods for removal of ethanol fore, many studies target the improvement of ethanol toler- during or after the fermentation process exist, however, while ance. Some recent and innovative approaches are highlighted efficient, current strategies are often costly or carry along un- here (see Zhao and Bai 2009; Snoek, Verstrepen and Voordeck- desired side effects, such as inferior aroma (Varela et al. 2015). ers 2016 for a more comprehensive overview). Natural variations Newer strategies aim to limit the amount of ethanol produced in MKT1 (a nuclease), SWS2 (a mitochondrial ribosomal protein) by the yeast, mainly by altering the central carbon flux or reg- and APJ1 (a chaperone with a role in SUMO-mediated protein ulating redox balance (Kutyna et al. 2010; Goold et al. 2017). For degradation), though not traditionally linked to ethanol toler- example, deletion of PDC1 or ADH1, the major ethanol produc- ance, account for the increased ethanol tolerance of the Brazil- tion line, reduces ethanol production (Nevoigt and Stahl 1996; ian bioethanol strain VR1 (Swinnen et al. 2012). Variations in Cordier et al. 2007). Overexpression of glycerol synthesis genes the metabolome, namely accumulation of valine via deletion of such as GPD1 and FPS1 shifts carbon flux away from ethanol and LEU4 and LEU9 (which encode for key enzymes connecting va- towards glycerol synthesis (Nevoigt and Stahl 1996; Remize, Bar- line to leucine synthesis) or reduction of inositol levels by dele- navon and Dequin 2001; Cambon et al. 2006; Cordier et al. 2007). tion of INM2 (involved in inositol biosynthesis), also effectively increase ethanol tolerance (Ohta et al. 2016). Global transcrip- Physiological and ecological roles of ethanol tion machinery engineering, a high-throughput genetic technol- ogy, was used to find variants of the global transcription factor Eukaryotic cells typically opt for respiration when possible as Spt1 with increased ethanol tolerance (Alper et al. 2006). The mu- it offers a higher yield of ATP per molecule of glucose. Cer- tated versions of this protein led to widespread transcriptional tain yeasts, including S. cerevisiae, opt to ferment even in the reprogramming when introduced in yeast, and some of the presence of oxygen (De Deken 1966). This so-called Crabtree resulting mutants demonstrated improved ethanol tolerance effect is paradoxical, as the energy yield is significantly lower. (Alper et al. 2006). Other high-throughput strategies, such as However, it is believed that the rate of ATP production (amount TALENs (transcription activator-like effector nucleases)-assisted per time) is actually higher through fermentation, allowing for multiplex editing and robot-assisted genome shuffling, have faster growth. Moreover, ethanol is highly toxic to most other also yielded improvements in strain ethanol tolerance (Snoek microbes, which may help yeast cells compete with faster- et al. 2015; Zhang et al. 2015c). Long-term evolution has also been growing competitors (Rozpedowska et al. 2011). Although much demonstrated as an effective measure to increase ethanol toler- of metabolic flux is diverted to ethanol, it is important to note ance. Turbidostat cultures grown continuously for over 2 years that a fraction of the carbon is still shuttled to the TCA cycle, with gradually increasing ethanol concentrations yielded toler- which forms important aroma precursors through reactions as- ant variants with mutations in PRT1 (subunit of the eukaryotic sociated with amino acid metabolism. translation initiation factor 3), VPS70 (involved in vacuolar pro- Ethanol production by fermenting yeast cells may also have tein sorting) and MEX67 (poly(A)RNA-binding protein involved in an indirect role in ecology. Several studies indicate that ethanol nuclear mRNA export) (Voordeckers et al. 2015). influences the behavior of insects that inhabit the same nat- Modification of glycerol synthesis can also affect ethanol pro- ural niches. Fruit flies are strongly attracted to rotting fruits duction. During anaerobic growth, glycerol serves as an ‘elec- due to high concentrations of fermentation products, including tron sink’ to re-oxidize NADH generated during biosynthesis ethanol (Becher et al. 2012). In fact, ethanol provides a nuanced and concentrations can reach up to 5 g/L during industrial fer- signal for preferential oviposition sites among closely related mentations (Nielsen et al. 2013). Deletion of glycerol synthesis Drosophila (Diptera: Drosophilidae) species. Ethanol tolerance of genes GPD1 and GPD2 directly decreases glycerol levels with a adult flies of different species seems to correlate with preference resultant increase in ethanol (Nissen et al. 2000). Natural varia- for ethanol-rich oviposition substrate (Sumethasorn and Turner tions of GPD1, HOT1 (a transcription factor involved in glycerol 2016). Drosophila melanogaster is highly ethanol tolerant and in synthesis), SSK1 (a phosphorelay protein involved in osmoreg- laboratory conditions will lay twice as many eggs on ethanol- ulation) and SMP1 (a transcription factor involved in osmotic rich media than the ethanol-sensitive D. mauritiana.Moreover, stress response) also result in decreased glycerol to ethanol ra- the same species from differing climates can demonstrate vari- tios during fermentation (Hubmann et al. 2013a,b). Additionally, ations in both ethanol tolerance and ovipositioning preference. Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S100 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Drosophila melanogaster from temperate populations, such as Eu- volatiles that make them more attractive to potential ani- rope, has higher ethanol tolerance than populations from Africa mal pollinators. The nectar of bertam palm (Eugessona tristis), (Zhu and Fry 2015) and higher ethanol concentrations increase a popular food source for several insects and small animals, ovipositioning frequency from the European fly, but reduced fre- can contain up to 3.8% ethanol (Wiens et al. 2008). Behavioral quency from African flies (Sumethasorn and Turner 2016). studies indicate that these nectar-seeking animals, specifically The effect of ethanol content on ovipositioning has also been the primate slow loris (Nycticebus coucana) and the lemur aye- linked to the presence of parasitic wasps. Drosophila melanogaster aye (Daubentonia madagascariensis), preferentially feed on nec- increases egg laying on ethanol-rich substrate when there are tar containing ethanol (Gochman, Brown and Dominy 2016). parasitic wasps in the vicinity (Kacsoh et al. 2013). Subsequently, Interestingly, aye-ayes have a mutation in their ADH4 gene eggs laid by the wasps suffer increased mortality if the host in- resulting in a 40-fold increase of their ethanol metabolism gests ethanol-rich substrates (Milan, Kacsoh and Schlenke 2012) compared to most of the primates, potentially explaining why and even dilute levels of ethanol can reduce the total number of they do not get intoxicated on the high-alcohol food (Carrigan parasitoid eggs laid in the larvae. The preference for an ethanol- et al. 2015). containing ovipositioning site can strongly depend on the presence of suitable, ethanol-free food sources nearby. When the alternative ethanol-free substrate is close, flies prefer the PRIMARY FERMENTATION METABOLITES: CO , ethanol-containing substrate. As distance increases, prefer- ACETALDEHYDE AND ACETIC ACID ence for the ethanol rapidly declines (Sumethasorn and Turner Biochemistry of CO , acetaldehyde and acetic acid 2016). Taken together, this suggests that fruit flies are contin- production uously reevaluating the relative positions of the available sub- strates, potentially to ensure survival. They seem to prefer harsh As mentioned, under fermentative (anaerobic) conditions, pyru- (ethanol-rich) environments to protect the eggs and freshly vate is diverted towards ethanol in a two-step process (Fig. 2). hatched larvae, but only if a suitable, less harsh food source is Pyruvate is first converted to acetaldehyde with concomitant re- nearby for the larvae to find. lease of carbon dioxide (CO ) by PDC. The two major PDC en- The use of microbially produced compounds is a relatively re- zymes, Pdc1 and Pdc5, are the major contributors to the de- cent and recurrent approach currently being used as attractants carboxylation activity in the cell and therefore directly con- for various biological pests, and several examples will appear trol levels of acetaldehyde and CO (Kulak et al. 2014). Pdc6 throughout this review. One very recent example of this tactic is primarily utilized during growth on non-fermentable carbon is the use of ethanol-containing mixtures against the avian par- sources (Hohmann 1991). One would expect then that in a PDC1 asite Philornis downsi (Diptera: Muscidae). This South American- deletion the levels of acetaldehyde to significantly drop. How- native fly has recently invaded the Galapagos and its larvae have ever, in certain conditions, deletion of this enzyme demon- been feeding on the nestlings of the famous Darwin’s finches strates an increase in acetaldehyde (Curiel et al. 2016). It is hy- (Kleindorfer and Dudaniec 2016). Philornis downsi adults feed on pothesized that Pdc5 can compensate for up to 70% of the re- fermented substrates, and ethanol plays a crucial role in guiding quired PDC activity, indicating a possible compensatory mech- them to the food source. When ethanol is mixed with acetic acid, anism to maintain flux towards acetaldehyde and subsequent it effectively and specifically attracts P. downsi over non-target ethanol production (Wang et al. 2015). Furthermore, Pdc5 has insects (Cha et al. 2016). Similarly, the combination of ethanol a higher specific activity which may allow it to directly com- and acetic acid has been suggested as a useful and inexpensive pete with the respiratory pyruvate dehydrogenase and may help lure for trapping other insects such as pathogen-carrying Mus- push more pyruvate towards ethanol (Agarwal, Uppada and cina stabulans (Diptera: Muscidae) and Fannia canicularis (Diptera: Noronha 2013). Muscidae) (Landolt, Cha and Zack 2015), as well as the corn pest Acetaldehyde can then continue towards ethanol via ADH ac- Carpophilus humeralis (Coleoptera: Nitidulidae) (Nout and Bartelt tivity, or it can be acted on by an aldehyde dehydrogenase (ALD) 1998). to produce acetic acid. Like the ADHs, there are several ALDs, Insects are not the only organisms to be affected by ethanol. further expanding the level of regulation centered around car- Originally thought to be solely soil dwelling, the nematode bon flux. If acetaldehyde is produced cytosolically, it can be acted Caenorhabditis elegans is frequently found in rotting fruits, stems on by Ald6 or Ald2; if produced in the mitochondria, it is con- and flowers (F elix and Braendle 2010). It is therefore likely that verted by Ald4 or Ald5. Additionally, an acetaldehyde molecule C. elegans larvae encounter ethanol from microbial fermenta- still covalently linked to the PDC complex (via the bound thi- tion in its natural environment. While high concentrations of amine pyrophosphate) can interact with an additional acetalde- ethanol (above 100 mM) result in slower development, decreased hyde to form acetoin (Fig. 2). fertility and shorter life span (Davis, Li and Rankin 2008), at lower concentrations, ethanol appears to have beneficial survival ef- fects, prolonging the lifespan of the stress-resistant larval stage Carbon dioxide in industry (Castro et al. 2012). Since the nematode larvae do not appear to actively seek out ethanol (Patananan et al. 2015), it is hypothe- While humans do not typically associate an odor with carbon sized that the ethanol could provide a temporary carbon source dioxide, its production is important in some industrial pro- to ensure the larvae survive until proper food sources are found. cesses and is detectable by other organisms (see Physiological Interestingly, ethanol can influence C. elegans negatively through roles of CO ). CO is responsible for the natural carbonation of 2 2 a complex multispecies interaction: the yeast-produced ethanol fermented beverages and adequate gas production is arguably can enhance the growth of several Acinetobacter species, and in the most important selection criterion for commercial baker’s turn make them more efficient to withstand and even kill their yeasts, as proper leavening requires rapid and sufficient CO natural predator, C. elegans (Smith, Des Etages and Snyder 2004). release (Randez-Gil, Cor ´ coles-Saez ´ and Prieto 2013). Therefore, Certain primates are also attracted to fermenting food. Com- most optimization for increased speed of CO production has plex microbial communities in nectar sources produce diverse been performed in bread yeasts. Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S101 Environmental parameters and CO production with improved freeze tolerance, without undesirable side effects in other fermentation properties (Teunissen et al. 2002). Most bread fermentations should only take 1–2 h which requires a quick onset of the fermentation process to rapidly and ef- Acetaldehyde and acetic acid in industry fectively produce large volumes of CO .Tothisend,various dough parameters can be adjusted to speed up CO production Acetaldehyde is the central intermediate between pyruvate and (Table 2). Optimization of the physiological state of the yeasts ethanol but it is also an important aroma compound. It is quan- before introducing them into the dough can drastically improve titatively the most abundant aldehyde in most fermented prod- leavening ability. This can be accomplished by pre-soaking and ucts including apple juice and spirits (Miyake and Shibamoto thus reactivating dry yeast prior to starting the bread fermenta- 1993), beer (Margalith 1981; Adams and Moss 1995), cider and tion (Gelinas 2010). Additionally, adjusting the way that the dried perry (Williams 1975), wine (Liu and Pilone 2000), cheese (Engels yeasts are produced, for example, by optimizing the medium in et al. 1997), yoghurt (Zourari, Accolas and Desmazeaud 1992)and which they are grown, the timing at which the yeast cells are ripened butter (Lindsay, Day and Sandine 1965). Production of harvested, or the specific drying protocol, can increase yeast via- acetaldehyde has direct influence on the final product’s aroma, bility and vitality during bread fermentations (Galdieri et al. 2010; levels of ethanol production, as well as product stability and tox- Rezaei et al. 2014). icology (Romano et al. 1994). At low levels, acetaldehyde provides a pleasant, fruity aroma and is a decisive aromatic compound of many sherry-type and port wines (Zea et al. 2015). However, it Genetic factors and CO production is also notorious for its undesirable green apple-like or grassy In general, the ability to ferment specific bread-associated sug- flavor when exceeding threshold levels. This threshold varies ars (namely maltose, glucose, sucrose, and fructose) has been drastically between matrices, with 10 μg/g (ppm) reported for alteredtoimprove CO production, or the leavening ability, of beer (Meilgaard 1982), 30 μg/g for cider (Williams 1974)and up baker’s yeast. One of the most common problems associated to 130 μg/g for certain wines (Berg et al. 1955). Chemical conver- with dough fermentation is the considerable lag between fer- sions during aging can also increase overall acetaldehyde con- mentation of preferred sugars, glucose and sucrose, and fer- centrations of fermented beverages over time (Vanderhaegen mentation of maltose, the principle fermentable sugar in bread et al. 2003). dough. Catabolite repression slows down the switch and sub- Apart from its direct effect on flavor, acetaldehyde arguably sequently lengthens leavening time (Gancedo 1998). Therefore, has even a more important role indirectly. The molecule is ex- genes associated with glucose repression and maltose utiliza- tremely reactive and can react with various other compounds. tion have often been strategically targeted for genetic mod- In red wines, for example, acetaldehyde influences various pa- ification (Osinga et al. 1989;Sun et al. 2012;Lin et al. 2014, rameters not directly linked to aroma. It can bind sulfur dioxide 2015b; Zhang et al. 2015a,b). Alternatively, maltose utilization (SO ), which drastically reduces the effectiveness of this antimi- can be improved by selecting mutants on medium containing crobial agent, thereby facilitating spoilage (Liu and Pilone 2000). fermentable maltose with non-metabolizable glucose analogs. Acetaldehyde can also react with tannins, which are naturally Such strategies yield strains with deficiencies in catabolite re- occurring polyphenols in grapes, to form irreversible, covalent pression that could co-consume glucose and maltose resulting bridges, resulting in a reduction of the dry, puckering mouth- in faster dough leavening (Randez-Gil and Sanz 1994;Rincon ´ feel (‘astringency’) that is associated with these compounds et al. 2001; Salema-Oom et al. 2011). Similar mutants could po- (Mercurio and Smith 2008). A similar condensation reaction be- tentially reduce the lag time in the beer brewing fermentations tween anthocyanins or between anthocyanins and tannins me- as well (New et al. 2014). Consecutive rounds of mass mating and diated by acetaldehyde-bridged complexes is observed, result- selection have also yielded commercial strains with improved ing in polymeric pigments that influence wine color. These maltose utilization (Higgins et al. 2001). highly stable complexes are not susceptible to SO bleaching Yeast encounter various severe stresses during bread fer- or changes in wine pH, and are therefore desired for color sta- mentations, such as high sugar and salt concentrations, which bility (Boulton 2001). Similarly, interactions between the antho- reduces their performance (Aslankoohi et al. 2013). Improve- cyanin malvidin 3-monoglucoside and catechins in the presence ments of general stress resistance of industrial yeast have been of acetaldehyde, which also influence color and color stability in shown to yield faster bread fermentations. This is generally red wine, were observed (Rivas-Gonzalo, Bravo-Haro and Santos- achieved by increasing production of glycerol and other small Buelga 1995). The central role of acetaldehyde in these reactions protective molecules such as proline and trehalose (Shima and even inspired researchers to experiment with exogenous addi- Takagi 2009). Overexpression of glycerol synthesis genes, such tion of acetaldehyde, yielding red wines with reduced astrin- as GPD1, increases glycerol accumulation and subsequent osmo- gency and more stable color (Sheridan and Elias 2015). tolerance (Aslankoohi et al. 2015). Modification of proline perme- Acetic acid is referred to, in industry, as volatile acidity ases (PUT4) or proline biosynthesis genes (PRO1) increases pro- or vinegar taint. While industrial Saccharomyces species can line accumulation and improves osmo-, cryo- and halotolerance produce acetic acid, the presence of high acetic acid concen- (Kaino et al. 2008; Poole et al. 2009; Sasano et al. 2012). Disrup- trations often indicates the presence of other species. High tion of trehalose degradation (NTH1, ATH1) or efflux ( FPS1)in- levels of acetic acid are typically associated with the respira- creases intracellular trehalose levels and improves freeze tol- tory metabolism of ethanol by acetic acid bacteria. However, erance (Shima et al. 1999;Izawa et al. 2004; Sasano et al. 2012; some yeasts, notably Brettanomyces spp., can produce acetic Sun et al. 2016). Overexpression of CAF16 and ORC6,two genes acid in aerobic conditions (Crauwels et al. 2015). This trait is that are upregulated during osmotic and cryostress, also im- highly strain and species dependent (Castro-Martinez et al. 2005; proves overall stress tolerance of the yeast during baking (Per ´ ez- Rozpedowska et al. 2011). One species, Brettanomyces bruxellensis, Torrado et al. 2010). Directed evolution has also been used to im- is so efficient at producing acetic acid, it has been proposed as a prove stress tolerance in baker’s yeast. Ultraviolet mutagenesis candidate organism for industrial production (Freer 2002; Freer, followed by 200 consecutive freeze–thaw cycles yielded mutants Dien and Matsuda 2003). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S102 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 2. Effect of environmental parameters on CO production. Parameter Condition Effect on CO production Reference Temperature Decrease storage T of Decrease Sasano et al. (2012) yeasted dough Dough mixing time Increase Increase Sahlstrom ¨ et al. (2004) Medium composition C source availability Increase Increase, however, risk for Sahlstrom ¨ et al. (2004) osmotic stress Salt Increase Decrease (stress), however, Lynch et al. (2009), Toyosaki better CO containment and Sakane (2013) Nutrient mixes (wheat bran) Supplementation Increase Hemdane et al. (2016) Enzyme (amylase) Supplementation Increase (more available Struyf et al. (2017) sugars) In specific cases, the presence of these acid-producing tathione (Chen et al. 2012), oxidation of acetaldehyde to acetic species is desired for the fermentation, but more commonly acid (Yao et al. 2012) or increasing pyruvate flux into the mito- acetic acid is a sign of spoilage. In wine, 0.2–0.4 g/L of acetic chondria (Agrimi et al. 2014; Bender, Pena and Martinou 2015; acid is acceptable, but above 1.2–1.3 g/L, it is considered a fault. Jayakody et al. 2016) has been shown to reduce levels of ac- In contrast, concentrations up to 1.5 g/L are common in Lambic etaldehyde. Strains selected for resistance to Adh2 inhibitor 4- beers and, in combination with bacterially produced lactic acid, methylpyrazole demonstrated decreased ADH2 expression and are crucial for the sour characteristics of Lambic (Witrick 2012). an 82% reduction in acetaldehyde production (Wang et al. 2013). Similarly, direct disruption of ADH2 reduces acetaldehyde by 68% (Wang et al. 2006). Environmental parameter effects on acetaldehyde and Reduction of volatile acidity is mainly a concern in the wine acetic acid production industry. Aerobic fermentation can cause excess levels of acetic High levels of acetaldehyde are undesirable in an industrial acid. Due to the complexity of this part of the metabolic path- context and some simple adjustments to fermentation param- way, direct disruption of associated genes can have multiple and eters have been suggested to alter the level of acetaldehyde sometimes undesired effects. Deletion of PDC1 or ALD6 can re- (Table 3). For example, acetaldehyde production in some wine duce acetate levels but significantly increases levels of acetalde- strains remains constant when fermented between 12 Cand hyde, limiting its applicability (Luo et al. 2013; Curiel et al. 2016). ◦ ◦ 24 C but drastically increases at 30 C (Romano et al. 1994). Sup- The previously mentioned overexpression of GPD1 effectively plementation of SO2 also induces acetaldehyde production, but decreases ethanol production but also leads to excessively high the underlying mechanisms are unknown (Herraiz et al. 1989; acetic acid levels in wine (Cambon et al. 2006). Combining this Herrero, Garc´ıa and D´ıaz 2003). overexpression with deletion of ALD6 reduces the acetic acid Since acetic acid has different sources in fermented bever- but also increases acetaldehyde and acetoin. This can be com- ages (yeast and bacteria), there are different strategies for tar- pensated by overexpression of BDH1, which diverts the excess geting its production. Here we focus on control of yeast-derived acetaldehyde and acetoin to 2,3-butanediol, which has no ef- acetic acid from two important yeast genera associated with fect on overall flavor and aroma (Fig. 2)(Ehsani et al. 2009). Less industrial fermentations (Table 3). Production by Brettanomyces direct approaches require less genetic compensation. For ex- can be controlled by reducing oxygen availability (Rozpedowska ample, deletion of AAF1, a transcriptional regulator of the ALD et al. 2011), supplementing the fermentation with antimicro- genes, reduces acetic acid levels without affecting acetaldehyde bial agents (Portugal et al. 2014) or applying electric currents production (Luo et al. 2013). Strains with mutations in YAP1,a (Zuehlke, Petrova and Edwards 2013). Production by Saccha- transcription factor involved in oxidative stress tolerance, also romyces can be reduced by promoting general growth. Acetic demonstrate reduced acetic acid levels (Yamamoto et al. 2000; acid production is driven by accumulation of NAD during glyc- Cordente et al. 2013). erol production (Eglinton et al. 2002) and increasing biomass (i.e. growth) can help regenerate the pool of NADH. Supplementation Physiological and ecological roles of CO , acetaldehyde of nitrogen or unsaturated fatty acids can promote yeast growth and acetic acid with a subsequent reduction in acetic acid (Varela et al. 2012). Re- Though not a distinguishable aroma for humans, other or- ducing glycerol production by lowering the sugar concentration ganisms have distinct sensory responses to carbon dioxide. In can also decrease the levels of acetic acid in the final product yeast populations, including S. cerevisiae,CO can mediate cell– (Bely, Rinaldi and Dubourdieu 2003). 2 cell interactions, inducing growth and budding of neighboring colonies (Volodyaev, Krasilnikova and Ivanovsky 2013). In Can- Genetic factors and acetaldehyde and acetic acid dida albicans, increasing concentrations of self-generated CO production causes the cells to undergo morphological changes and switch Given the central role of acetaldehyde in carbon metabolism to hyphal growth (Hall et al. 2010). Interestingly, this mechanism (Fig. 2), it is not a straightforward task to specifically modu- has been implicated in the pathogenicity of C. albicans,asthe late its production. However, attenuation of ethanol metabolism switch to filamentous growth is important for biofilm formation (Wang et al. 2013), increasing acetaldehyde scavenging via glu- and invasive growth in the host (Hall et al. 2010;Lu et al. 2013). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S103 Table 3. Effect of environmental parameters on acetaldehyde, and acetic acid production. Effect on acetaldehyde Parameter Condition production Reference Temperature Increase Increase Romano et al. (1994) Oxygen Increase Increase Branyik et al. (2008), Curiel et al. (2016) Medium composition Csource Non-fermentable Increase Romano et al. (1994) SO Increase Increase Jackowetz et al. (2011) Effect on acetic acid production Brettanomyces Oxygen Increase Increase (direct effect on Rozpedowska et al. (2011) production) Medium composition Antimicrobial agents (sulfite, chitosans, ...) Supplementation Decrease (inhibits growth) Portugal et al. (2014) Weak acids and sorbic acid Supplementation Decrease (inhibits growth) Wedral et al. (2010) Low electric current Application of ∼200 mA Decrease (inhibits growth) Zuehlke et al. (2013) Pulsed electric field Application of ∼30 Decrease (inhibits growth) Zuehlke et al. (2013) kV/cm, 1–4 μs pulses Saccharomyces Temperature Decrease Decrease Beltran et al. (2008) Oxygen Increase Increase Curiel et al. (2016) Medium composition C concentration Increase Increase (glycerol Bely et al. (2003) production, redox imbalance) Nsource Supplementation Decrease (stimulates yeast Bely et al. (2003), Barbosa growth, provides NADH) et al. 2009 Copper Supplementation Increase Ferreira et al. (2006) Yeast lees and insoluble material Increase Variable (some lead to Delfini and Costa ( 1993) increase, others to decrease) Accumulation of acetaldehyde in yeast cells results in growth 2004; Turner and Ray 2009). Recent studies indicate that this re- inhibition and a stress response (Stanley et al. 1993; Aranda and pulsion highly depends on the behavioral context, i.e. whether Olmo 2004). When acetaldehyde diffuses out of the cell, it acts the flies are walking on surface or flying in the air (Wasserman, as a volatile signaling molecule. At high cell densities, yeast cells Salomon and Frye 2013). When in flight, Drosophila melanogaster coordinate their metabolism by sensing the secreted acetalde- are attracted to CO , possibly due to modulations of neurotrans- hyde, resulting in collective macroscopic oscillations and syn- mitters which occur during flight (Orchard, Ramirez and Lange chronized phases of growth (Richard et al. 1996). Interestingly, 1993). The current hypothesis is that in crowded conditions, several cellular systems, from yeast colonies to human muscle, when flies are gathered on a surface, CO is repulsive but when and even tumors, demonstrate this type of synchronized oscil- in flight and searching for food, CO can act as an attractive sig- lations of glycolytic reactions (Betz and Chance 1965; Tornheim nal to indicate the presence of fermenting fruits. and Lowenstein 1974; Nilsson et al. 1996;Richard 2003;Fru et al. Acetic acid is also an important volatile for mediating the 2015). behavior of D. melanogaster. This fruit fly is reported to have a Acetic acid is potentially used by Brettanomyces as a strat- highly selective olfactory neuron for detection of acids which egy to outcompete other microbes (Rozpedowska et al. 2011). is generally connected with observed acid-avoiding behavior The ‘make-accumulate-consume’ strategy allows Brettanomyces (Ai et al. 2010). However, D. melanogaster is also known to be lured yeast to accumulate high levels of acetic acid which dramatically by acetic acid (Hutner, Kaplan and Enzmann 1937; Knaden et al. lowers the pH of the environment. Since this yeast has a higher 2012), which accounts for its attraction to vinegar and nickname tolerance for low pH than most microbes, it can withstand the as the ‘vinegar fly’. Females looking for ovipositioning sites are extreme environment and later consume the acetic acid as an strongly attracted by acetic acid, whereas flies not ready to de- extra carbon source. posit eggs show little or no attraction (Joseph et al. 2009;Gou These three compounds also play an important role in in- et al. 2014). The closely related species, D. simulans,isrepulsed sect behavior. Acetaldehyde is a core component of a compound by microbially produced acetic acid; this behavior strongly corre- blend used to attract and trap pest beetles from the genus Car- lates with the increasing acid concentration (Gunther ¨ et al. 2015). pophilus (Phelan and Lin 1991; Nout and Bartelt 1998). In sev- These examples suggest a complexity in the perception and pro- eral reports, CO had a repulsive effect on fruit flies (Suh et al. cessing of sensory information, both gustatory and olfactory, 2 Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S104 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 3. Production of vicinal diketones. The vicinal diketones are produced as by-products during the isoleucine-leucine-valine (ILV) biosynthetic pathways. Gene names correlate with nomenclature from S. cerevisiae (Saccharomyces Genome Database). OYE = ‘Old Yellow Enzyme’. Dotted lines indicate import/export, solid lines indicate biochemical reactions. Note: dotted line from sugar to pyruvate also encompasses glycolysis. to modulate behavior. In this example, it has been hypothe- of acetohydroxybutyrate forms 2,3-pentanedione. Towards the sized that the egg-laying preference on acetic acid-containing end of fermentation, these compounds can be reabsorbed by the substrates depends on gustatory inputs (females will taste the cell and converted to acetoin (and subsequently 2,3-butanediol) acetic acid when on the surface). However, when not in direct and 3-hydroxy-2-pentanone by various reductases (van Bergen contact with the medium, olfactory information only leads to et al. 2016). aversion of acetic acid-containing food (Joseph et al. 2009). To- gether with ethanol, acetic acid has also been found as an im- portant volatile to attract flies such as Fannia canicularis, Muscina Vicinal diketones in industry stabulans and Philornis downsi (Diptera: Muscidae) to fermenting substrates as a food source (Landolt, Cha and Zack 2015; Cha Vicinal diketones can provide a pleasant nutty, toasty and toffee- like flavor in fermented foods and beverages, most notably beer, et al. 2016). Furthermore, when acetic acid is combined with other fermentation compounds, such as phenylacetaldehyde, wine and dairy products (Molimard and Spinnler 1996;Bar- towsky and Henschke 2004; Krogerus and Gibson 2013a). How- stronger attraction of insects is achieved (Becher et al. 2010, 2012; Cha et al. 2012). ever, they are considered off-flavors when present in high con- centrations, changing their sensory perception to ‘buttery’ or ‘rancid’. Especially in beer brewing, vicinal diketone production AMINO ACID METABOLITES: VICINAL is an ongoing challenge. Diacetyl is rarely perceived positively DIKETONES in beer, except in a few specific styles (e.g. sour ales, Bohemian Pilsner and some English ales). Biochemistry of vicinal diketone production Diacetyl is generally more of a focus in industrial beer fer- mentation than 2,3-pentanedione for two reasons. First, it has Vicinal diketones (i.e. compounds containing two adjacent a significantly lower sensory threshold (0.1 μg/g versus 1.0 μg/g) carbon-oxygen double bonds) can be produced during fermen- which makes it more detectable in the final product. Second, the tation through non-enzymatic decarboxylation of intermediates direct connection between diacetyl and pyruvate has implica- in the valine and isoleucine anabolic pathways (Fig. 3). Dur- tions in managing ethanol production levels. In wine, diacetyl is ing fermentation, pyruvate can be converted to various carbon considered less of a problem and low (1–4 μg/g) concentrations compounds such as acetolactate. The acetolactate can then be positively contribute to desirable buttery or butterscotch notes. diverted towards synthesis of valine and leucine. Inefficiency Moreover, excessively high concentrations are rare but rather in- of the valine biosynthesis pathway during growth results in a dicate bacterial spoilage or other irregularities during malolactic buildup of acetolactate which is then secreted into the medium. fermentation (Bartowsky and Henschke 2004). Additionally, di- Similarly, during isoleucine biosynthesis, acetohydroxybutyrate acetyl is masked in part by the presence of SO in wine which is produced and is also secreted. Both compounds are non- 2 results in a marked increase in threshold levels (Bartowsky and enzymatically converted to diketones: decarboxylation of aceto- Henschke 2004). lactate forms diacetyl (2,3-butanedione) while decarboxylation Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S105 Table 4. Effect of environmental parameters on vicinal diketone production. Parameter Condition Effect on vicinal diketone production Reference Temperature Increase Decrease during fermentation or Bamforth and Kanauchi (2004) maturation (higher cell density, more acetolactate to diacetyl conversion) pH Decrease Increase (increased enzyme efficiency) Bamforth and Kanauchi ( 2004) Fermentation time Increase Decrease (more acetolactate to Bamforth and Kanauchi (2004) diacetyl conversion and diacetyl reduction) Oxygen Increase Decrease (higher cell density) Portno (1966) Medium composition Valine supplementation Increase Decrease (less acetolactate Krogerus and Gibson (2013b) production, see Figure 2) Sugar concentration Increase Decrease Saerens et al. (2008b) Enzyme (α-Acetolactate decarboxylase) Supplementation Decrease (acetolactate to acetoin Godtfredsen and Ottesen (1982) conversion) Environmental parameters and vicinal diketone 2012). Heterologous expression of a bacterial acetolactate decar- boxylase gene (ALDC) catalyzes the non-oxidative decarboxyla- production tion of acetolactate to acetoin and bypasses diacetyl production Due to the highly reductive conditions that exist at the end of (Kronlof and Linko 1992). alcoholic fermentations, the concentration of diacetyl is usu- ally below (or close to) its sensory detection threshold in fresh Physiological and ecological roles of vicinal diketones beer (Haukeli and Lie 1972). Diacetyl reduction effectively elimi- nates the undesired flavors as acetoin and 2,3-butanediol do not As described, production of the vicinal diketones is done ex- contribute to the aroma profile. Therefore, some beers are sub- tracellularly following the secretion of accumulated acetolac- jected to a maturation phase of 2–3 weeks after fermentation tate and acetohydroxybutrate. The biological role of this phe- to allow any residual acetolactate to decarboxylate and subse- nomenon is not known, but protection from carbonyl stress and quently be reduced by the yeast to below its detection limit. subsequent cellular damage has been suggested (van Bergen This maturation phase requires storage capacities and limits et al. 2016). Additionally, the reduction of the diketones is phys- the output of beer from a brewery and the economic feasibil- iologically favorable for yeast, as the resulting end products are ity. Therefore, there have been some considerable efforts to find + + less toxic and the reactions replenish the NAD and NADP alternative ways to reduce natural diacetyl formation or speed pools (De Revel and Bertrand 1994). up diacetyl reduction by modifying various process parameters Diacetyl has a ‘masking’ role in ecological settings rather (Table 4). than a direct role as a signaling molecule. Drosophila melanogaster The connection to amino acid metabolism directly affects has high specificity neurons for detecting diacetyl and CO synthesis of these two compounds; if nitrogen is low and the (de Bruyne, Foster and Carlson 2001). As discussed earlier, cell needs to synthesize its amino acids, production of these CO can elicit avoidance behavior in fruit flies, which seems by-products will also increase (Krogerus and Gibson 2013a). somewhat counterintuitive, since CO is a signal of ferment- Simply supplementing fermentation media with exogenous va- ing fruit, a suitable food source and ovipositioning site. Diacetyl line can dramatically decrease production of diacetyl (Krogerus masks the avoidance signal by blocking the receptor, result- and Gibson 2013b). Since the conversion of acetolactate to di- ing in attraction to the fermentation source (Turner and Ray acetyl is non-enzymatic, heating after fermentation increases 2009; Turner et al. 2011). A reversed interplay is observed in the rate of conversion of excess acetolactate, which can subse- several mosquito species, where mosquitoes are attracted to quently be reduced (Kobayashi et al. 2005). The use of a contin- CO which is then blocked by the presence of diacetyl (Turner uous fermentation setup minimizes yeast growth, and thus va- et al. 2011). line biosynthesis, and reduces formation of diacetyl (Verbelen et al. 2006). AMINO ACID METABOLITES: HIGHER Genetic factors and vicinal diketone production ALCOHOLS Perhaps the most well-characterized biochemical pathway in Arguably one of the most promising and cheaper strategies to re- yeast aroma production is the Ehrlich pathway. This is likely due duce vicinal diketones is modification of yeast metabolism. Most to the very desirable and recognizable compounds produced by commonly, this is done by increasing the metabolic flux from this pathway—the higher (fusel) alcohols and subsequently, the acetolactate to valine or promoting conversion of acetolactate acetate esters. Felix Ehrlich first posited the connection between to acetoin. Mutation of ILV2 (acetolactate synthase) reduces di- amino acid metabolism and higher alcohol formation in 1907 acetyl formation by 64% (Wang et al. 2008). Similarly, increased based on their structural similarity (Fig. 4). This led to a sim- expression of ILV5 (acetohydroxyacid reductosiomerase), the ple, classic experiment of varying the concentration of specific rate-limiting step in valine synthesis, reduces diacetyl forma- amino acids in the fermentation media and noting changes in tion 50%–60% (Mithieux and Weiss 1995; Kusunoki and Ogata Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S106 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 4. The Ehrlich pathway. There are several routes that can direct carbon compounds into the production of amino acids and subsequently the higher alcohols. This scheme depicts the most direct connections between the amino acids and the respective higher alcohols through the three-step Ehrlich Pathway (general reactions depicted at top). Dotted lines indicate multiple steps. Note: the reduction step can be carried out by over 10 different enzymes which vary in localization, regulation and substrate specificity; AdhX = alcohol dehydrogenase (Adh1, Adh2, Adh3, Adh4, Adh6, Adh7); AadX = aryl alcohol dehydrogenase (Aad3, Aad4, Aad6, Aad10, Aad14, Aad15, Aad16). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S107 production of the corresponding fusel alcohols (Ehrlich 1907). Reduction Over the next century, the details of this biochemical process At this point, the fusel aldehydes can undergo an oxidation or have been greatly uncovered leading to significant improve- a reduction. The various ADHs and AADs catalyze the reduc- ments in the fermentation industry. tion step and complete the Ehrlich pathway. Any one of the ADH enzymes can catalyze this last step, but research indicates that Adh1 and Adh2 mainly participate in ethanol metabolism (de- scribed above). If the fusel aldehydes undergo an oxidation re- Biochemistry of higher alcohol production action by an ALD, they are converted into their respective fusel The Ehrlich pathway is a three-step process that modifies assim- acids. ilated amino acids, the major source of nitrogen in many fer- mentation processes. In general, amino acids are deaminated, Higher alcohols in industry decarboxylated and finally reduced to their respective alcohol derivatives (Fig. 4). By sequentially modifying amino acids, yeast Higher alcohols can impart a much-desired effect on the prod- cells can harvest and utilize the essential nitrogen as needed uct’s flavor despite their higher sensory threshold, which can and in turn produce an array of fragrant and distinct aroma com- differ several orders of magnitude compared to their corre- pounds (Hazelwood et al. 2008;Pires et al. 2014). Given the chem- sponding acetate esters. The major fusel alcohols found in al- ical similarities of the intermediates to pyruvate, acetaldehyde, coholic beverages are 1-propanol (alcoholic aroma), 1-butanol and ethanol, many of the same enzymes involved in production (alcoholic), isobutanol (alcoholic), 2-phenylethanol (roses, flow- of the primary fermentation metabolites are also involved in this ery) and isoamyl alcohol (banana, fruity). pathway. The rose-like fragrance of 2-phenylethanol has made it a desirable compound for use in many perfumes, cosmetics and beverages (Etschmann et al. 2002). Currently, the greater part Transamination of its commercial production is done synthetically, but this After uptake from the media, amino acids are converted to their process requires use of carcinogenic precursors, such as ben- respective α-keto acid by a transaminase capable of transferring zene and styrene, and yields various difficult-to-remove by- amine groups between amino acids. In Saccharomyces cerevisiae, products. It is possible to extract 2-phenylethanol from the es- there are six enzymes capable of this type of reaction: Bat1, sential oils of plants, but this process is excessively expen- Bat2, Aat1, Aat2, Aro8 and Aro9 (SGD, Cherry et al. 2012). Aat1 sive due to low yields (Etschmann et al. 2002). Therefore, re- and Aat2 do not play a role in higher alcohol production; these searchers have turned to microbial production of this compound enzymes act specifically on aspartate as part of the malate- (Carlquist et al. 2015). Genetically modified or mutagenized aspartate shuttle to move electrons from the cytosol to the mi- Saccharomyces cerevisiae strains have been utilized to convert tochondria for respiratory energy production (Cronin et al. 1991; phenylalanine into 2-phenylethanol, typically by enhancing the Morin, Subramanian and Gilmore 1992). The other four enzymes Ehrlich pathway (Kim, Cho and Hahn 2014). Non-conventional have been directly linked to higher alcohol synthesis but, as seen yeasts have also been explored as production strains includ- with the ADHs discussed above, each contributes differently to ing Kluyveromyces marxianus, which naturally produces more 2- the Ehrlich pathway. Bat1 and Bat2 are primarily involved with phenylethanol than S. cerevisiae (Ivanov et al. 2013). Additionally, transamination of the branched chain amino acids, whereas K. marxianus grows quickly and is thermotolerant making it an Aro8 and Aro9 are aromatic amino acid transaminases acting on interesting candidate for commercial production (Etschmann, phenylalanine and tryptophan, respectively (Kispal et al. 1996; Sell and Schrader 2003; Gao and Daugulis 2009; Morrissey et al. Iraqui et al. 1998). 2015). The associated fusel acids are also of industrial interest. The production of these compounds can be perceived posi- Decarboxylation tively or negatively depending on the context. In soy sauce, The second step of the Ehrlich pathway is the irreversible de- flor-forming strains of Zygosacharomyces rouxii can produce carboxylation of the α-keto acid to an aldehyde. The same three 2-methylpropanoic acid (isobutyric acid) and 3-methylbutanoic PDCs used in the production of acetaldehyde (Pdc1, Pdc5 and acid (isobutyric acid) (corresponding alcohols isobutanol and Pdc6) have all been implicated in the production of the fusel isoamyl alcohol), compounds associated with foul, spoiled aro- aldehydes. Additionally, Aro10 is capable of this reaction, and mas. In some cases, metabolic engineering approaches have is primarily responsible for decarboxylating 2-phenylpyruvate been employed to actually increase production of these acids. to 2-phenylacetaldehyde (Vuralhan et al. 2003). Aro10 is also a Short branched-chain fatty acids such as 2-methylbutanoic acid, likely candidate for some variations in higher alcohol produc- isobutyric acid and isovaleric acid are valuable compounds in tion between species. Saccharomyces kudriavzevii produces more the food and pharmaceutical industries. The acids and their higher alcohols than S. uvarum or S. cerevisiae (Stribny et al. derivatives can be used as fragrances and flavorings (Yu et al. 2016). ScAro10 prefers phenylpyruvate but SkAro10 has a broader 2016). substrate preference, almost equally acting on phenylpyruvate, ketoisocoaproate, ketoisovalerate, ketomethylvalerate and even Environmental parameters and higher alcohol keto-γ -methylthiobutyrate (Stribny et al. 2016). Interestingly, the production interspecies hybrid, S. pastorianus, harbors three copies of the S. cerevisiae ARO10 gene and one copy from S. eubayanus. While The three-step process described above is situated amongst a both isozymes prefer phenylpyruvate as a substrate, SeuAro10 complex network of amino acid metabolism: there are multi- has much higher activity towards ketoisovalerate (Bolat et al. ple paths to each of the major alcohols that require significant 2013). Copy number variation and slight discrepancies in sub- regulation and balance during the fermentation process. Addi- strate preference add a level of aroma complexity to hybrid tionally, levels of each compound are dramatically affected by brewing yeasts. the medium composition, especially carbon source and nitrogen Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S108 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 5. Effect of environmental parameters on higher alcohol production. Effect on higher alcohol Parameter Condition production Reference Temperature Increase Increase Landaud et al. (2001) Oxygen Increase Increase Valero et al. (2002) Medium composition Csource Maltose Decrease (compared to sucrose, Younis and Stewart (1998) fructose, glucose) Sugar concentration Increase Decrease (not always) Younis and Stewart (1999) N source (total) Increase Decrease (co-regulation of LEU and Yoshimoto et al. (2002) BAT genes) NH Supplementation Decrease Vidal et al. (2013) Amino acids Supplementation Increase in respective higher Hernandez-Orte et al. (2005) alcohol (see Fig. 3) Vitamins Supplementation Increase Etschmann et al. (2004) Maillard compounds Increase Increase Dack et al. (2017) sources (Table 5). Since higher alcohols are mainly produced dur- 2016) but its overexpression causes an increase in production of ing active growth, factors that positively influence yeast growth higher alcohols (Kim, Cho and Hahn 2014). These conflicting re- simultaneously promote higher alcohol synthesis (Dekoninck sults could be due to a multitude of factors including differences 2012). If there is a surplus of exogenous amino acids, as shown in strain background or variations in media used for fermenta- by Ehrlich and others, production of these alcohols increases tions. Regardless, this points to a significantly more complicated (Ehrlich 1907;He et al. 2014). If amino acids are in short supply, relationship between the aminotransferases that may help con- the pathways will inevitably favor anabolic routes. This under- tribute to the diversity of higher alcohol production in different standing has been adopted by industry as a powerful way to di- strains. rect higher alcohol production (Etschmann et al. 2002;Vidal et al. As becomes apparent from the previous examples, sophisti- 2013; Lei et al. 2013a). cated metabolic engineering is needed to obtain highly produc- tive strains for higher alcohols. Several research teams focus on butanol isomers as these compounds can be used as alternative fuels. An exhaustive overview of metabolic engineering strate- Genetic factors and higher alcohol production gies for butanol isomer production has recently been published Engineered yeast strains for increased higher alcohol produc- elsewhere (Generoso et al. 2015). But, despite the extensive ef- tion are utilized both for increasing concentrations of the forts to improve the production yield of butanol isomers (and alcohols themselves and their respective esters. Overexpres- higher alcohols in general) in S. cerevisiae, the efficiency that can sion of ADH6 can increase isobutanol production (Kondo et al. be achieved by metabolic engineering is still significantly lower 2012) whereas overexpression of ADH1 can increase levels of compared to other hosts, such as Escherichia coli. Comparison 2-phenylethanol (Shen et al. 2016). Our understanding of the of central metabolism of metabolically engineered E. coli and S. ILV biosynthetic and Ehrlich pathways allows for complex, mul- cerevisiae revealed that flexibility of this metabolism is an im- tistep metabolic engineering to increase specific higher alco- portant factor in efficient production of butanols and propanols hols. For example, overexpression of ILV2, ILV3, and ILV5 in- (Matsuda et al. 2011). creases the flux towards isoleucine production (Fig. 3). If this is coupled with deletion of BAT1 (transaminase) and ALD6 (the aldehyde dehydrogenase) plus overexpression of ARO10 Physiological and ecological roles of higher alcohols and ADH2 (both alcohol dehydrogenases), the α-keto acid and aldehyde derivatives of isoleucine are pushed towards produc- Given the significant variation in higher alcohol production from tion of the higher alcohol (Fig. 4) (Park, Kim and Hahn 2014). different yeasts, it is perhaps not surprising that insects have Conversely, deletion of the alcohol dehydrogenase ADH with developed an ability to utilize these compounds as chemical overexpression of BAT1, ALD2 and ALD5 increases the produc- signatures. Many insect olfactory receptors are specifically at- tion of the fusel acids by diverting flux at the last Ehrlich tuned to the detection of higher alcohols and many of these step towards oxidation. These acids are also intermediates for compounds can elicit antennal and behavioral responses in in- production of value-added products in the chemical industry sects (Hallem and Carlson 2004; Saerens, Duong and Nevoigt (Yu et al. 2016). 2010; Knaden et al. 2012;Witzgall et al. 2012). It has been demon- Due to the complexity and intricate nature of these path- strated on several occasions that cultures of the yeast-like fun- ways, simple mutation does not always have the desired ef- gus Aureobasidium pullulans can lure a variety of insects, in- fect. For example, some studies show that deletion of ARO8 cluding hoverflies (Diptera: Syrphidae) (Davis and Landolt 2013) (one of the aromatic amino transferases) increases catabolism and social wasps (Vespula spp. (Hymenoptera: Vespidae) (Davis, of phenylalanine to its higher alcohol 2-phenylethanol (Romag- Boundy-Mills and Landolt 2012). In both cases, a synthetic blend noli et al. 2015;Shen et al. 2016) while others have demonstrated of higher alcohols, namely 2-methyl-1-butanol, isoamyl alco- that overexpression of the same gene also increases produc- hol and 2-phenylethanol, proved to be even more attractive to tion of higher alcohols (Yin et al. 2015;Wang et al. 2016b). Ad- the insects than the yeast culture. The wasps are known to ditionally, deletion of ARO9 has no apparent effect (Shen et al. act as vectors for A. pullulans, suggesting a strong interaction Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S109 between the wasps and the yeast species (Davis, Boundy-Mills whereas the longer hydrocarbon tails of fatty acid ethyl esters and Landolt 2012). reduce their capacity to diffuse across the membrane. There- Compound blends to mimic fermenting yeasts are com- fore, acetate esters impart significantly more influence over monly being implemented to combat agricultural pests. Many flavor and fragrance than the fatty acid counterparts. of the blends contain higher alcohols since these tend to assist Ester synthesis is carried out by alcohol-O-acetyl (or acyl)- in eliciting antennal responses and attraction. The beetle Car- transferases (AATases). In Saccharomyces cerevisiae, there are four pophilus humeralis infests and damages corn crops, and higher known enzymes: Atf1 and Atf2 are responsible for most acetate alcohol-containing blends are designed to mimic S. cerevisiae fer- ester production and Eeb1 and Eht1 synthesize the fatty acid menting corn and lure them (Nout and Bartelt 1998). The re- ethyl esters (SGD, Cherry et al. 2012). There is definitive evidence lated beetle, C. hemipterus, is similarly attracted to S. cerevisiae- that there are additional enzymes of both types in S. cerevisiae. produced higher alcohols, namely 2-pentanol, isoamyl alcohol, Double deletion of ATF1 and ATF2 results in complete loss of isobutanol and butanol (Phelan and Lin 1991). The weevil Arae- isoamyl acetate production but only a 50% reduction in ethyl ac- cerus fasciculatus (Coleoptera: Anthribide), a coffee bean pest, etate (Verstrepen et al. 2003c). Similarly, a double deletion of EEB1 was recently found to be attracted to 2-phentylethanol imply- and EHT1 does not eliminate fatty acid ethyl esters (Saerens et al. ing that the compound might serve as a potential lure (Yang et al. 2006). 2016). Recently, a third ethyl acetate-forming enzyme has been de- Higher alcohols can also serve as directory signals for insects. scribed (Kruis et al. 2017). The ethanol acetyltransferase 1 (Eat1) Fermentations of S. cerevisiae or a synthetic blend of five fer- was identified in Wickerhamomyces anomalus and defines a new mentation compounds, including ethanol, isoamyl alcohol and family of enzymes which is distinct from the canonical AATases. 2-phenylethanol, is sufficient to attract D. melanogaster (Becher Eat1 is actually a hydrolase that can perform thioesterase and et al. 2012). Among other compounds, higher alcohols produced esterase reactions in addition to formation of ethyl acetate. Ho- by Metschnikowia, including isoprenol, 2-phenylethanol and cit- mologs are found in several ethyl acetate-producing yeasts. Al- ronellol, can elicit antennal responses in the codling moth Cy- though a triple deletion has not yet been attempted, deletion of dia pomonella (Lepidoptera: Tortricidae) (Witzgall et al. 2012). The the S. cerevisiae Eat1 homolog, YGR015C, results in a 50% reduc- moths utilize the emitted aromas to orient themselves towards tion in ethyl acetate production, which complements the Atf1 suitable oviposition sites, such as yeast-infested apples that pro- and Atf2 production. vide a food source for larvae and protection from harmful fungal The enzymatic activities of these enzymes can differ sig- infestations. nificantly, even more so between different species and strains, Some higher alcohols have antifungal properties. Isoamyl al- adding to the variation of the final fermentation product. For cohol produced by Candida maltosa inhibits the germination of example, Atf1 has equal substrate specificity for isoamyl alco- filamentous fungi (Ando et al. 2012). Pichia anomala produces hol and 2-phenylethanol whereas Atf2 prefers isoamyl alcohol 2-phenylethanol potentially as a biocontrol agent against As- (Stribny et al. 2016). However, both Atf1 and Atf2 from S. kudri- pergillus a fl vus; the compound inhibits spore germination and avzevii or S. uvarum, have higher preference for 2-phenylethanol the production of the carcinogenic mycotoxin produced which compared to the S. cerevisiae homologs. This is directly re- can contaminate the crops P. anomala grows on (Hua et al. 2014). flected under fermentation conditions, where strains harboring Kloeckera apiculata likewise produces 2-phenylethanol to inhibit S. kudriavzevii and S. uvarum enzymes produce much more 2- growth of various Penicillium molds (Liu et al. 2014). Other stud- phenylethyl acetate. ies have also demonstrated anti-fungal effects of yeast volatiles from various species (several Candida species, S. cerevisiae, A. pul- Esters in industry lulans, Metschnikowia pulcherrima), but the specific effector com- pounds have not yet been identified (Fiori et al. 2014; Parafati et al. Esters are generally accepted as some of the most important 2015; Lemos Junior et al. 2016). contributors to the flavor and aroma of alcoholic beverages, Several higher alcohols such as 2-phenylethanol, tryptophol, imparting fruity and flowery notes to the product (Nordstr om ¨ tyrosol and farnesol can act as quorum-sensing molecules in di- 1966; Verstrepen et al. 2003a). During industrial fermentations, morphic yeasts, including S. cerevisiae, Debaryomyces hansenii and yeasts produce esters in very low concentrations, often only a Candida albicans. Secretion of the alcohols regulates the switch few parts per billion (ppb) (Lambrechts and Pretorius 2000). In- between unicellular yeast forms and filamentous forms (Chen cidentally, these natural concentrations hover around the fla- et al. 2004; Chen and Fink 2006; Gori et al. 2011). Moreover, it has vor threshold for humans and consequently, small changes in been speculated that these quorum-sensing molecules can play ester production can significantly alter perception of the prod- a role on the population level and influence the establishment of uct. There is a synergistic effect in the perception of many es- microbial communities in (semi-) spontaneous fermentations, ters, where a mixture of compounds will highlight or mask the such as wine, lambic beers and/or cheese, but evidence for such presence of others (Nordstrom ¨ 1964a; Suomalainen 1971). How- interactions is still lacking (Ciani and Comitini 2015). ever, an excess of esters often results in an unpalatable prod- uct, highlighting the importance of balance in the production of aroma compounds (Liu, Holland and Crow 2004). AMINO ACID METABOLITES: ESTERS The overall importance and complexity of ester production has led to considerable industrial research to optimize produc- Biochemistry of ester production tion. Interestingly, these compounds affect the quality of prac- Esters are formed by a condensation reaction between tically all food fermentations that involve yeasts, ranging from acetyl/acyl-CoA and an alcohol (Fig. 5). The use of acetyl- fermented beverages (Lilly, Lambrechts and Pretorius 2000;Ver- CoA or acyl-CoA divides esters into two different categories, strepen et al. 2003a), over bread (Birch et al. 2013; Aslankoohi et al. acetate esters and fatty acid ethyl esters, respectively. The small 2016), to chocolate (Meersman et al. 2016). Moreover, biotech- size and lipophilic nature of acetate esters allow them to readily nological production of high ester concentrations, especially diffuse from the cytoplasm into the extracellular medium ethyl acetate, has been studied for several years. Ethyl acetate Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S110 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 5. Ester synthesis in yeast. Left: general scheme of both types of ester production. Esters are the result of condensation reactions between an alcohol and an acetyl/acyl-CoA. (A) Acetate esters are produced through the actions of Atf1 and Atf2. (B) Fatty acid esters are produced by Eeb1 and Eht1. Right: examples of some of the most common esters discussed in this review. General aroma descriptors are listed in italics. is an environmentally friendly solvent with many industrial pression of ATF1 and BAT1 and subsequently alter ester levels applications but its production involves energy-intensive petro- (Saerens, Thevelein and Delvaux 2008). chemical processes. Several non-conventional yeasts, more In general, higher temperatures result in higher alcohol pro- specifically W. anomala, Candida utilis and especially duction and subsequent acetate ester production (Landaud, La- Kluyveromyces marxianus, all species with inherently high trille and Corrieu 2001) though this effect can vary given differ- ethyl acetate production, have been explored (Loser ¨ , Urit and ences in fermentation matrix, genetic background and the es- Bley 2014). ters of interest (Molina et al. 2007;Birch et al. 2013). Additionally, ATF1 and ATF2 expression are positively correlated with temper- ature and would result in increases in acetate ester production Environmental parameters and ester production (Saerens et al. 2008b). However, the volatile nature of acetate es- There are a multitude of parameters that can influence ester ters would lead to an overall decrease in concentration at exces- production in yeast which allows for significant modulation of sively high temperatures. This is the case in chocolate produc- the ester profile of foods or beverages without genetic manipu- tion; during post-fermentation processing, the chocolate mass lation (Table 6). However, given the complexity of the regulation is subjected to an hour-long mixing at temperatures as high as of enzyme and substrate availability, the exact outcome of mod- 75 C (Meersman et al. 2016). This production step results in the ifying one specific parameter is still hard to predict. In general, loss of many yeast-derived aroma compounds, including acetate acetate and ethyl ester production are often affected in the same esters. However, fatty acid esters, which dissolve more easily way by the same parameters (Saerens et al. 2008a). into the fat fraction of chocolate, are largely retained. The concentration and composition of fermentable carbon Dissolved oxygen and unsaturated fatty acids are negative sources as well as the carbon-to-nitrogen ratio have dramatic ef- regulators of ATF1 expression and, consequently, ester synthe- fects on ester production (Table 6) (Piddocke et al. 2009; Dekon- sis (Dufour, Malcorps and Silcock 2003). Interestingly, both com- inck et al. 2012). The direct connection to higher alcohols and pounds are shown to act on the same part of the ATF1 promo- their amino acid precursors makes ester production highly de- tor, namely the low-oxygen response element (Jiang et al. 2001). pendent on the nitrogen source. The concentration of free amino Therefore, oxygenation of the fermenting medium is a power- nitrogen (FAN), including amino acids and small peptides, pos- ful and straightforward tool to modulate ester production. How- itively correlates with acetate ester production (Procopio et al. ever, it is not always feasible to increase or decrease the oxygen 2013; Lei et al. 2013a, b). Increased nitrogen can also increase ex- content of the medium, as it can have undesirable side effects Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S111 Table 6. Effect of environmental parameters on ester production. Parameter Condition Effect on ester production Reference Temperature Increase Increase (not always) Molina et al. (2007), Saerens et al. (2008a) Oxygen Increase Decrease (decreased expression of Fujii et al. (1997), Anderson and Kirsop (1974) ester synthesis genes) Medium composition Unsaturated fatty acids Increase Decrease (decreased expression of Fujii et al. 1997, Anderson and Kirsop (1974) ester synthesis genes) Free amino nitrogen (FAN) Increase Increase (precursor availability Saerens et al. (2008a), Lei et al. (2013ba) and increased expression of ester synthesis genes) Sugar concentration Increase Increase (increased expression of Saerens et al. (2008b) ester synthesis genes) Csource Glucose, fructose, sucrose Increase (compared to maltose) Verstrepen et al. (2003b), Piddocke et al. (2009) Maillard compounds Increase Decrease Dack et al. (2017) Hydrostatic pressure Increase Decrease (increased dissoved CO ) Landaud et al. (2001), Meilgaard (2001) (e.g. irregular yeast growth, impaired flavor stability or increased isoamyl alcohol and isoamyl acetate (Oba et al. 2005). Similarly, risk of contamination). Adding unsaturated fatty acids can be growth with phenylalanine analogues (o-fluoro- and p-fluro- an interesting alternative without the undesired effects (Moon- DL-phenylalanine) selects for 2-phenylethyl acetate producers jai et al. 2002). (Fukuda et al. 1990, 1991). There have been interesting attempts Modifications to the fermentation vessel can alter the yeast to selectively enhance variations in either ATF1 or ATF2 given the cells’ microenvironment and affect physiological changes. A variations in which types of acetate esters are produced. Growth shift from small fermenters to tall, cylindroconical vessels in with farnesol analogs (1-farnesylpyridinium) favors Atf1 activity large breweries resulted large decreases in ester production (Hirooka et al. 2005), while supplementing medium with preg- (Meilgaard 2001). This was explained by the increased concen- nenolone favors Atf2 activity (Tsutsumi et al. 2002; Kitagaki and tration of dissolved carbon dioxide which inhibited overall de- Kitamoto 2013). In the latter example, the harmful steroid is me- carboxylation reactions, resulting in lower substrate levels for tabolized by Atf2 and therefore selects for strains with enhance- ester production (Landaud, Latrille and Corrieu 2001). ments of Atf2 activity. Those mutants would be able to increase levels of isoamyl acetate without affecting ethyl acetate. Experimental evolution utilizing lipid synthesis inhibitors has also resulted in strains with enhanced ester production. Se- Genetic factors and ester production lection on aureobasidin, a sphingolipid biosynthesis inhibitor, As acetate esters are quantitatively the most abundant group of resulted in mutations in MGA2 which has been implicated in esters in industrial fermentations, and are shown to have a ma- ATF1 regulation (Takahashi et al. 2017). Growth on cerlulin, a jor impact on flavor, it is not surprising that researchers have of- fatty acid synthesis inhibitor, selected for mutants of FAS2,a ten aimed to hijack the yeast’s ester production to diversify the fatty acid synthetase, with enhanced production of ethyl es- organoleptic characteristics of many diverse fermented foods. ters and the additional benefit of reduced acetic acid levels (see The total ester production and the relative proportions of each Fig. 5)(Ichikawa et al. 1991). A self-cloning sake strain equipped individual ester differs dramatically between species and strains with this mutation became the first genetically modified mi- (Steensels et al. 2014a; Padilla, Gil and Manzanares 2016). Thus, croorganism approved for industrial use in Japan (Aritomi et al. the most straightforward way to vary ester levels in fermenta- 2004). tion is to vary the yeast strain. Metabolic engineering to control ester formation has mostly targeted ATF1 and ATF2 expression or activity (Lilly, Lambrechts and Pretorius 2000; Hirosawa et al. Physiological and ecological roles of esters 2004; Lilly et al. 2006; Swiegers et al. 2006). Modulating expression of IAH1, an esterase, also affects ester concentrations (Lilly et al. The physiological role of ester production in yeast has been 2006; Zhang et al. 2012). Sexual hybridization has also been suc- under debate for several decades. It has been hypothesized cessfully applied to modulate ester production. Breeding meth- that ester synthesis helps to tune intracellular redox balance ods have helped increase and diversify ester production of com- (Malcorps and Dufour 1992) and that some esters help to mercial ale (Steensels et al. 2014a), lager (Mertens et al. 2015), maintain plasma membrane fluidity under stressful conditions sake (Yoshida et al. 1993; Kurose et al. 2000), wine (Bellon et al. (Mason and Dufour 2000). Additionally, esterification of toxic 2013) and even chocolate (Meersman et al. 2016). medium-chain fatty acids may facilitate their removal from cells Since formation of these compounds does not necessarily via diffusion through the plasma membrane (Nordstrom ¨ 1964b). impart a fitness advantage, there is no straightforward way While the intracellular roles are not quite understood, recently to select for desired ester production in experimental evolu- it has become clear that esters have significant roles extracellu- tion, mutagenesis or breedings set ups. Therefore, other ap- larly. proaches have been developed to select for enhanced esters. Of the many volatile compounds produced by yeast, esters Growth in the presence of a leucine analog (5,5 ,5 -trifluor-DL- represent one of the most important groups that can act as leucine) selects for variants with reduced positive feedback on insect semiochemicals, signaling the presence of rotting fruits leucine production which results in increased production of (El-Sayed et al. 2005). Fruity esters such as isoamyl acetate, ethyl Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S112 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 acetate and 2-phenylethyl acetate represent the core attractants which puts it in proximity to its potential host, D. melanogaster of various insects (Davis et al. 2013; Christiaens et al. 2014;Schei- (Dicke et al. 1984). dler et al. 2015). Deletion of ATF1 in S. cerevisiae significantly Similar to the higher alcohols, esters can have antifungal ef- reduces attraction of Drosophila melanogaster and simple re- fects, possibly to eliminate competition for the yeasts producing addition of isoamyl acetate or ethyl acetate can restore the flies’ them. Pichia anomala, P. kluyveri or Hanseniaspora uvarum all se- behavior (Christiaens et al. 2014). Isoamyl acetate is also respon- crete 2-phenylethyl acetate which can strongly inhibit growth sible for attraction of D. simulans, but the attraction is strongly and mycotoxin production by the fungus Aspergillus ochraceus dependent on the background chemical matrix (Gunther ¨ et al. (Masoud, Poll and Jakobsen 2005). 2015). There are also examples of possible species-specific re- sponses to various ester compounds. Drosophila suzukii has a AMINO ACID METABOLITES: SULFUR significantly higher response to isobutyl and isoamyl acetate, whereas D. melanogaster responds to ethyl hexanoate (Keesey, COMPOUNDS Knaden and Hansson 2015; Scheidler et al. 2015). The herbivo- The generic classification of ‘sulfur-containing’ opens a large rous drosophilid, Scaptomyza flava, a relative of D. melanogaster, and diverse array of compounds to consider including ev- has lost its ability to detect most yeast volatiles (Goldman- erything from basic thiols (such as hydrogen sulfide or Huertas et al. 2015). Genes encoding for neuronal receptors re- methanethiol) and sulfides (dimethyl sulfide, dimethyl disulfide, sponsible for detecting esters are either deleted or have loss etc.), thioethers and thioesters, sulfur-containing aldehydes and of function mutations in S. a fl va , demonstrating the important alcohols, as well as larger, polyfunctional thiols. Given the exten- connection between yeast volatiles and locating microbial food sive list of potential compounds, we focus on the assimilation of sources. sulfur, the connections to amino acid metabolism and industri- The black calla lily (Arum palaestinum) has taken advantage of ally relevant sulfur compounds. the drosophilids’ ability to detect esters. This plant has evolved to mimic yeast fermentation volatiles specifically by producing 2,3-butanediol acetate and acetoin acetate to lure drosophilids Biochemistry of sulfur assimilation and metabolism for pollination (Stokl ¨ et al. 2010). Recent evidence indicates that interactions within the D. All yeast-produced sulfur compounds arise during the melanogaster microbiome can alter behavior of the fly (Fischer catabolism or anabolism of the sulfur-containing amino et al. 2017). While the flies feed on yeasts, lactic and acetic acid acids methionine and cysteine. Since these amino acids are bacteria are major constituents of its gut microbiome. In fer- found at relatively low concentrations in both natural and menting fruits, all three microorganisms co-exist and the grow- industrial environments, yeasts are required to assimilate inor- ing microbes create a collaborative volatile profile which en- ganic sulfur via the sulfate reduction sequence (Fig. 6). Sulfates hances attraction of D. melanogaster. Acetate esters (isobutyl ac- are sequentially reduced to sulfide which can combine with etate, isoamyl acetate, 2-phenylethyl acetate, 2-methylbutyl ac- a nitrogen source (O-acetyl-serine or O-acetyl-homoserine) etate, methyl acetate, ethyl acetate) along with acetic acid and to form cysteine and subsequently, methionine. From this acetoin were determined as the key compounds in this interac- point, the amino acids can be incorporated into protein or tion (Fischer et al. 2017). re-metabolized to form other volatile sulfur compounds. In In combination with higher alcohols, esters can be attractive cases of low nitrogen, the amount of available O-acetyl-serine for agricultural pests such as the coffee bean weevil Araecerus or O-acetyl-homoserine is limited, and there is an overproduc- fasciculatus (Coleoptera: Anthribidae) and Carpophilus beetles as tion of sulfide. This is converted to hydrogen sulfide to allow they mimic volatiles of fermenting fruits (described in the pre- for diffusion out of the cell (Jiranek, Langridge and Henschke vious section) (Phelan and Lin 1991; Nout and Bartelt 1998;Yang 1995; Spiropoulos et al. 2000; Mendes-Ferreira, Mendes-Faia et al. 2016). Codling moths Cydia pomonella, a common apple pest, and Leao ˜ 2002; Swiegers and Pretorius 2005). Additionally, it utilizes esters and other aroma compounds emitted by Metch- has recently been shown that some sulfur compounds, such nikowia yeasts to locate suitable ovipositioning sites (Witzgall as ethanethiol, S-ethyl thioacetate and diethyl disulfide, can et al. 2012). be synthesized from excess H S, independent of methionine In addition to insects, the earthworm Eisenia fetida uses synthesis (Kinzurik et al. 2016). volatile cues, such as ethyl pentanoate and ethyl hexanoate, to From newly synthesized or exogenously added methionine navigate towards its food source Geotrichum candidum, a yeast- and cysteine, all other volatile sulfur compounds can be pro- like mold frequently used in the dairy industry (Zirbes et al. duced. Some of these pathways have not been fully mapped in 2011). Additionally, esters emitted by S. cerevisiae, such as methyl S. cerevisiae, but a general scheme can be drawn based on stud- acetate, ethyl acetate, propyl acetate, butyl acetate and amyl ies done on sulfur pathways in bacteria and other yeast species acetate, have strong attractive effects on nematode worms (Fig. 6). Bacteria have been more widely studied in regard to sul- (Balanova et al. 1979). fur production since the negative odors are generally associated Yeast-produced esters can also mediate host–parasite inter- with spoilage or desired aromas in specific types of cheese which actions. Honey bees produce isoamyl acetate-containing alarm utilize lactic acid bacteria (Kieronczyk et al. 2003). Tracing stud- pheromones that defend the hive against several predators and ies and genetic engineering attempts to manipulate levels of H S parasites. The beetle Aethina tumida (Coleoptera: Nitidulidae) is and the more desirable sulfur compounds have provided insight attracted to the isoamyl acetate. The beetles can vector the yeast into potential biosynthetic pathways (Arfi, Landaud and Bonn- Koamaea ohmeri to the hive which then begins to ferment and arme 2006; Cordente et al. 2012). produce more isoamyl acetate in high concentrations. This am- Cysteine and methionine breakdown has been linked to plifies the attraction of beetles and results in a vast infestation of dimethyl sulfide (DMS) production but it can also be formed beetles and larvae, causing enormous damage to the hive (Torto from the reduction of dimethyl sulfoxide (DMSO) by Mxr1 (me- et al. 2007). Similarly, the parasitic wasp Leptopilina heterotoma is thionine sulfoxide reductase) (Hansen 1999). For most other attracted to ethyl acetate (along with ethanol and acetaldehyde) sulfur-containing compounds, methanethiol is considered the Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S113 Figure 6. Sulfate reduction pathway leading to the production of sulfur-containing amino acids and compounds. (1) Extracellular sulfate is taken up through two transporters, Sul1 and Sul2, and sequentially reduced to sulfite and sulfide. (2) Excess sulfide can be converted to hydrogen sulfide which diffuses out o f the cell or (3) assimilated into amino acid synthesis pathways. (4) Production of α-ketobutyrate links this pathway to threonine and the branched amino acid synthesis pathways (Fig. 2). (5) Methionine can be acted on by a lyase to form methanethiol, which is a major precursor for numerous sulfur-containing aroma compounds. (6) Methanethiol can also be produced via transamination of methionine, which is also the first step of the Ehrlich pathway (Fig. 3). Adapted from Landaud (2008), Pereira et al.(2008), and Saccharomyces Genome Database (Cherry et al. 2012). primary precursor. Two different pathways lead to the produc- There is an important category of sulfur-containing com- tion of methanethiol: the lyase pathway or the transamina- pounds that are not directly synthesized by yeast. Polyfunctional tion pathway (Fig. 6, step 5). Demethiolation of methionine by thiols are present in the biomass used for fermentation but as a lyase is more comprehensively understood in bacteria but it non-volatile precursors. The cystathionine lyases Cys3, Irc7 and does occur in yeasts (Landaud, Helinck and Bonnarme 2008). Str3 release the polyfunctional thiols from the cysteine conju- The transamination pathway is essentially the Ehrlich pathway. gates (Tominaga et al. 1998;Howell et al. 2005; Holt et al. 2011; The intermediate keto-γ -methylthiobutyrate (also referred to as Roncoroni et al. 2011). 4-methylthio-2-oxobutyric acid or MOBA) can undergo a vari- ety of chemical and enzymatic reactions including conversion to Sulfur compounds in industry methanethiol. If MOBA continues via the Ehrlich pathway, there is subsequent production of methional, then methionol (via re- Sulfur compounds are most relevant in beer, wine and cheese- duction) or methylthio-propionic acid (via oxidation). Cysteine making industries. Unlike fusel alcohols or esters, some sulfur can also undergo conversion to the respective higher alcohol, compounds are classified as positive while others are considered 2-mercaptoethanol. Methanethiol can be produced through ox- negative odors. For example, the classic ‘rotten-egg’ odor usually idation or acylation reactions (Landaud, Helinck and Bonnarme associated with sulfur comes from hydrogen sulfide (H S) while 2008). furfurylthiol smells of roasted coffee. Other negative sulfur Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S114 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Table 7. Effect of environmental parameters on sulfur compound production. Effect on sulfur compound Parameter Condition production Reference Temperature Increase Increase (thiols) Howell et al. (2004), Masneuf-Pomarede et al. (2006) pH Decrease Decrease (H S, methanethiol, Bekker et al. (2016) DMS) Oxygen (fermentation) Increase Decrease (H S, methanethiol, Bekker et al. (2015) ethanethiol, methylthioacetate, ethylthioacetate, DMS) Oxygen (post-bottling) Increase Decrease (H S, methanethiol) Ugliano et al. (2012) Medium composition Copper sulfate Supplementation Decrease (H S and thiols; Kreitman et al. (2016) oxidation) N source (total) Increase Decrease (H S; dependent on Mendes-Ferreira et al. (2010), Spiropoulos et al. (2000) timing and methionine concentration) Botrytis cinerea infection Increase Increase (thiols) Thibon et al. (2010) compounds include methanethiol (cooked cabbage), sulfides Perhaps one of the most common problems in the wine in- (cabbage, cauliflower, garlic) and methylthioesters (cheesy, dustry is finding a balance between limiting production of the chives) (Cordente et al. 2012). Interestingly, the perception of undesirable H S while increasing levels of aroma-enhancing these compounds is highly context specific. While DMS typically volatile thiols. Complete wine fermentations are sometimes smells of cabbage, it can convey desired aroma notes to lager treated with copper sulfate, a process referred to as copper fin- beers and whiskey (Anness and Bamforth 1982; Hansen et al. ing, which effectively removes H S (Clark, Wilkes and Scollary 2002). Similarly, some of the sulfur-containing aromas are pro- 2015). However, the copper only requires presence of a free thiol duced by yeasts on the surface of soft cheeses and contribute to group to form a stable complex and will therefore also decrease their distinctive odor (Landaud, Helinck and Bonnarme 2008). levels of desirable thiol compounds. Furthermore, this strategy Some aroma-enhancing volatile thiols are produced by wine is ineffective in removing several sulfuric off-odors that lack a yeast from precursors present in grape must. Of interest are free thiol group, such as disulfides, thioacetates and cyclic sul- 4-mercapto-4-methylpentan-2-one (4MMP), 3-mercaptohexan- fur (Kreitman et al. 2016). 1-ol (3MH) and 3-mercaptohexyl acetate (3MHA), which impart Oxygenation both during fermentation or post-bottling can box tree (4MMP), passionfruit, grapefruit, gooseberry and guava also influence volatile sulfur compound profiles in wine. aromas (3MH and 3MHA) on the wine (Tominaga et al. 1998; Oxygen treatment during fermentation can reduce concentra- Dubourdieu et al. 2006). tions of H S, methanethiol and ethanethiol (Bekker et al. 2015). Sulfites can act as an antioxidant in wine and beer as well The effect of exposure after bottling is dependent on oxygen as protect against bacterial and Brettanomyces spoilage (Suzzi, ingress through the bottle cap or cork. More porous closures al- Romano and Zambonelli 1985; Divol, Toit and Duckitt 2012). low for some gas exchange and are correlated with lower H S However, sulfites produced by yeast are at relatively low lev- and methanethiol levels (Ugliano et al. 2012). DMS and DMDS els since they are reduced to be incorporated into amino acids. levels are unaffected; however, desirable volatile thiols are also Therefore, these are sometimes added prior to bottling to help reduced and are thus better conserved in air-tight conditions stabilize the final product. compared to oxygen permeable conditions (Lopes et al. 2009). Genetic factors and sulfur compound production Environmental parameters and sulfur compound Sulfur compound production widely varies between S. cerevisiae production strains and other species. Genetic engineering strategies have Since several sulfur compounds are considered to negatively targeted several of the genes associated with sulfur assimila- affect product quality, several strategies have been developed tion (Fig. 6). Mutation of MET5 or MET10 blocks the conversion to reduce their emission (Table 7). Low nitrogen conditions in- of sulfite to sulfide and reduces H S production (Sutherland crease the yeast cell’s need for amino acids which would in- et al. 2003; Cordente et al. 2009; Linderholm et al. 2010; Bisson, crease general sulfur assimilation. This leads to increased pro- Linderholm and Dietzel 2013). Overexpression of the cystathio- duction of H S so it has been common practice for decades to nine synthetase CYS4 also reduces H S production by driving 2 2 add nitrogen sources to fermentation medium (Jiranek, Lan- the sulfide towards amino acid synthesis (Tezuka et al. 1992). gridge and Henschke 1995; Mendes-Ferreira, Mendes-Faia and Mutating MET14 limits sulfur assimilation overall (Donalies and Leao ˜ 2004). However, this effect is dependent on the timing of Stahl 2002). Additionally, mutations in MET2 (produces O-acetyl- supplementation, yeast strain and the presence of methionine homoserine) or SKP2 (a potential regulator of sulfur assimilation (Spiropoulos et al. 2000; Mendes-Ferreira et al. 2010;Barbosa, genes) increase levels of sulfite and H S (Hansen and Kielland- Mendes-Faia and Mendes-Ferreira 2012). The strongest decrease Brandt 1996; Yoshida et al. 2011). DMS levels can be reduced by in H S levels is obtained when nitrogen source is added concur- disrupting MXR1, which prevents the conversion of DMSO to rently with methionine. DMS (Hansen et al. 2002). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S115 Table 8. Effect of environmental parameters on phenolic compound production. Effect on phenolic compound Parameter Condition production Reference Brettanomyces Medium composition Antimicrobial agents (sulfite, chitosans, ...) Supplementation Decrease (inhibits growth) Portugal et al. (2014) Weak acids and sorbic acid Supplementation Decrease (inhibits growth) Wedral et al. (2010) Low electric current Application of ∼200 mA Decrease (inhibits growth) Zuehlke et al. (2013) Pulsed electric field Application of ∼30 kV/cm, Decrease (inhibits growth) Zuehlke et al. (2013) 1–4 μs pulses Saccharomyces Temperature Increase Increase Vanbeneden (2007), Cui et al. (2015) Medium composition Csource Glucose Increase (compared to fructose, Vanbeneden (2007) maltose, sucrose, galactose) Csource Fructose, maltose, sucrose Increase (compared to galactose); Vanbeneden (2007) decrease (compared to glucose) Csource Galactose Decrease (compared to glucose, Vanbeneden (2007) fructose, maltose, sucrose) Top pressure Increase Decrease (increase in dissolved CO)Vanbeneden(2007) Fermentation practice Top cropping Decrease (less yeast sedimentation) Vanbeneden (2007) Enhanced release of aromatic thiols from biomass precur- which are trained by humans to locate underground truffles sors can be achieved by variations in the lyases, specifically the (Talou et al. 1990). β-lyases IRC7 and STR3.Many S. cervisiae strains have 38 bp dele- tion in the IRC7 gene, resulting in low levels of 4MMP. Strain PHENOLIC COMPOUNDS selection for β-lyase activity or overexpressing STR3 or a full- length copy of IRC7 greatly enhances 4MMP and 3MH release Biochemistry of phenolic compound production (Holt et al. 2011; Roncoroni et al. 2011;Belda et al. 2016). Pre-treatment of various lignin polymers of plant cell walls is a common practice in the fuel and beverage industries. The bioprocessing of these polymers prior to the fermentation pro- Physiological and ecological roles of sulfur compounds cess releases a variety of furans, carboxylic acids and phenolic compounds which can greatly inhibit microbial growth (Klinke, Hydrogen sulfide plays an important role in the physiology of Thomsen and Ahring 2004). Many microbial species, such as yeast cells. As described above in the acetaldehyde section, yeast Saccharomyces cerevisiae, Aspergillus niger, Pseudomonas aeruginosa cells exhibit glycolytic oscillations, in which they coordinate and Escherichia coli, counteract the negative impact by convert- their metabolism. Hydrogen sulfide can also cause respiration ing these compounds into less toxic molecules. For example, inhibition and therefore plays a role in regulating respiratory os- vanillin, a phenolic guaiacol, can be detoxified by conversion to cillations (Sohn, Murray and Kuriyama 2000; Lloyd and Murray vanillyl alcohol by yeast Adh6 (Wang et al. 2016a). Several of the 2006). hydroxycinnamic acids, such as cinnamic acid (phenylacrylic Methionol has been shown to activate an olfactory response acid), caffeic acid, ferulic acid and p-coumaric acid, can be decar- neuron in D. melanogaster (de Bruyne, Foster and Carlson 2001) boxylated to less toxic phenolic compounds which have a large and attract the fruit flies (Farhadian et al. 2012; Knaden et al. 2012) impact on industrial fermentations (Fig. 6). but concentrations used in those studies were higher than what In S. cerevisiae, there are two enzymes essential for decar- is typically produced by fermenting yeasts. However, it has been boxylation of the hydroxycinnamic acids encoded by PAD1 and shown that natural levels of methionol from vinegar and wine FDC1 (phenylacrylic acid decarboxylase and ferulic acid decar- elicit an antennal response from D. suzukii and when mixed with boxylase). For several years, it was unclear how the genes inter- other compounds (acetic acid, acetoin and ethanol) it effectively acted to produce phenolic compounds. In some studies, PAD1 attracts the flies (Cha et al. 2014). This indicates that methionol was assumed to be the sole responsible enzyme for this reac- could play a relevant ecological role in yeast–drosophilid com- tion as deletion or mutation resulted in complete loss of activity munication. but it was clearly demonstrated that both PAD1 and FDC1 are re- Truffles host various yeast and bacteria and while the pro- quired for the decarboxylation of hydroxycinnamic acids (Mukai duction of volatile compounds overlaps between the species, it et al. 2010). It has now been shown that PAD1 possesses no de- has been speculated that yeasts contribute to the truffle aroma, carboxylase activity but instead is responsible for formation of largely defined by sulfuric compounds such as DMS, DMTS and a modified flavin mononucleotide (FMN) which is required for 3-(methylsulfanyl)-propanal (Buzzini et al. 2005; Vahdatzadeh, FDC1 decarboxylase activity (Lin et al. 2015a;Payne et al. 2015; Deveau and Splivallo 2015). DMS is one of the defining cues for White et al. 2015). pigs, which use truffles as a food source, as well as for dogs, Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S116 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 Figure 7. Production of phenolic compounds. Hydroxycinnamic acids are released during pre-processing of biomass. Yeast cells can decarboxylate these toxic com- pounds to less harmful forms through the actions of Fdc1. Fdc1 requires a cofactor FMN which is produced by Pad1. The compounds are then secreted and can be further reduced by a vinylphenol reductase, typically by contaminating yeast or bacterial species. Phenolic compounds in industry on the precursor availability in the fermentation medium. In- creased precursor concentrations not only increase substrate During fermentation, the actions of Pad1 and Fdc1 convert fer- availability but also activate transcription of PAD1 and FDC1 ulic acid, p-coumaric and caffeic acid to 4-vinylguaiacol (4-VG), (Vanbeneden 2007). Other fermentation parameters, such as 4-vinylphenol (4-VP) and 4-vinylcatechol (4-VC), respectively temperature and carbon source, have been shown to affect for- (Fig. 7). Subsequently, these compounds can be reduced to form mation of phenolic compounds, but the underlying mechanisms 4-ethylguaiacol (4-EG), 4-ethylphenol (4-EP) and 4-ethylcatechol are not understood (Vanbeneden 2007;Cui et al. 2015). (4-VC) by vinylphenol reductase (Vanderhaegen et al. 2003;Van- beneden, Delvaux and Delvaux 2006; Hixson et al. 2012). Both 4-VG and 4-EG are associated with more pleasant clove-like or Genetic factors and phenolic compound production spicy aromas, while 4-VP and 4-EP aromas are considered more medicinal and ‘Band-Aid’-like. As Saccharomyces generally lacks Surprisingly few attempts have been performed to modify phe- reductase activity, 4-EG, 4-EP production during fermentation nolic compound production in industrial strains. This is due is an indicator of the presence of Brettanomyces (Steensels et al. in part to the simplicity of their production and the fact that 2015). These phenolic compounds are significant contributors to many industrial yeasts have already acquired natural mutations fermentation aromas but their role is ambiguous. In certain spe- to block phenolic compound production. It has recently been es- cialty beer styles, such as wheat, Hefeweizen, Lambic, American tablished that selection for PAD1 and FDC1 loss-of-function mu- coolship ale and acidic ale beer, the phenolic flavors are desired tants is one of the key drivers in the domestication of industrial and help define the style. However, the same compounds are S. cerevisiae lineages associated with beer and sake production perceived negatively in most other fermented beverages and are (Gallone et al. 2016; Gonc¸alves et al. 2016). This selection is not commonly referred to as ‘phenolic off-flavors’ (POF) (Vanbene- observed in baking or bioethanol strains as in these cases, phe- den 2007). nolic compounds are likely less detrimental, either because the flavor disappears during baking or the product is not destined for consumption. Additionally, for strains used in beer styles Environmental parameters and phenolic compound where phenolic compounds are desired, selection for mutations in these genes is not observed. production Given the general association as ‘off-flavors’, several aspects of the fermentation process have been modified to reduce pheno- Physiological and ecological roles of phenolic lic compound production (Table 8). The undesired presence of compounds Brettanomyces during fermentation can be attenuated by various inhibitors (e.g. sulfites or chitosans) or electric currents. Produc- The POF-negative character of many industrial yeasts is espe- tion of phenolic compounds by Saccharomyces heavily depends cially striking since the phenotype is preserved in all wild strains Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 Dzialo et al. S117 Figure 8. Summary of the ecological roles of aroma compounds. This review has summarized a variety of physiological and ecological roles of yeast aroma compounds. This figure depicts some of the major organisms described to illustrate the vast number of compounds that they interact with. Positive ( +) indicates a generally positive interaction such as attraction, increased growth or behavior. Negative (–) indicates a negative interaction such as inhibited growth or repulsion. that have currently been analyzed, which indicates a strong fit- Low oxygen enhances activity of the vinylphenol reductase ness advantage of these genes in natural environments (Gallone (Fig. 7) and subsequently reduces levels of its cofactor, NADH et al. 2016). Since hydroxycinnamic acids are antimicrobial com- (Curtin et al. 2013). pounds, the ability of some yeasts to convert these acids to less Drosophila melanogaster uses volatile ethyl phenols as indica- harmful phenolic compounds provide them with resistance and tors for the presence of hydroxycinnamic acids which are potent promotes growth (Baranowski et al. 1980; Larsson, Nilvebrant dietary antioxidants. Since the insects do not possess the ability ¨ ¨ and Jonsson 2001; Richard, Viljanen and Penttila 2015). Addition- to detect the acids directly, they have developed specialized ol- ally, formation of the ethyl derivatives could play a role in main- factory neurons for detecting the ethyl phenols instead (Dweck taining redox balance in the cell in oxygen-limited conditions. et al. 2015). Downloaded from https://academic.oup.com/femsre/article/41/Supp_1/S95/4084365 by DeepDyve user on 19 July 2022 S118 FEMS Microbiology Reviews, 2017, Vol. 41, No. Supp 1 CONCLUSION et al. 2015). Though we know quite a lot about individual aroma compounds, the complex interactions between them are rela- Humans realized the potential of fermentation several thousand tively understudied. Additionally, it is likely that there are more years ago, and have since been exploiting the natural versatility aroma compounds to be identified, especially in an ecological of yeast aroma production. Fermented foods and beverages pro- context. Moreover, it is yet unclear if the insect and animal re- vide several advantages including longer shelf lives and a pleas- cipients perceive the compounds discretely or as a blend. Such ing euphoric effect. Over time, the procedures for fermentations interactions could also be interesting from a human perspective became more sophisticated and more refined. Eventually, other especially in the case of bioremediation in agriculture, where uses for fermentation became apparent and the use of yeast for microbial-produced compounds can be exploited as insect re- industrial purposes sparked a whole new field of research and pellants or attractants. The plethora of already observed inter- development. There is now genetic evidence that demonstrates actions that are influenced by aroma compounds illustrates that how much humans have driven the evolution of industrial yeast aroma-producing microbes may play important, yet underesti- species to select for desired aroma traits (Gallone et al. 2016, mated roles in the ecosystem. Gonc¸alves et al. 2016). Moreover, in the past few decades, new technologies have significantly advanced and refined the selec- tion process (Steensels et al. 2014b). We now utilize specific yeast ACKNOWLEDGEMENTS strains to produce biofuels, pharmaceutical compounds, flavors The authors would like to thank all Verstrepen laboratory mem- and fragrant additives. bers, especially Karin Voordeckers, for their help and sugges- Selection for specific aromas has also been observed in nat- tions. ural strains (Gallone et al. 2016) but in some cases, wild yeasts maintain some aromas that humans have deemed undesirable. There are also species-specific enhancements of various aroma FUNDING compounds through small variations in the biosynthetic genes. The authors also acknowledge funding from the Belgian This leads to questions about what possible physiological roles American Education Foundation (MCD), KU Leuven (RP and the different aroma compounds may have and whether there JS). KJV also acknowledges funding from an ERC Consolida- are fitness advantages to produce them. tor Grant CoG682009, HFSP program grant RGP0050/2013, KU Microbial aroma compound production is important in both Leuven NATAR Program Financing, VIB, EMBO YIP program, industrial and ecological settings. Aroma compounds very of- FWO, and VLAIO. ten signal desirability or identify potentially harmful conditions. In many cases, the physiological role of aroma formation re- Conflict of interest. None declared. mains unknown, but several hypotheses have been proposed. Some aromas are simply by-products of detoxification of other- wise harmful compounds, such as the conversion of hydroxycin- REFERENCES namic acids and esterification of toxic medium chain fatty acids Adams MR, Moss MO. Food Microbiology. Cambridge, UK: Royal (Nordstrom ¨ 1964b, Klinke, Thomsen and Ahring 2004). 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Physiology, ecology and industrial applications of aroma formation in yeast

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