TY - JOUR
AU - Karl-Josef, Dietz,
AB - Abstract Forty years ago, 12-oxophytodienoic acid (12-OPDA) was reported as a prostaglandin (PG)-like metabolite of linolenic acid found in extracts of flaxseed. Since then, numerous studies have determined the role of 12-OPDA in regulating plant immunity, seed dormancy, and germination. This review summarizes our current knowledge of the regulation of 12-OPDA synthesis in the chloroplast and 12-OPDA-dependent signaling in gene expression and targeting protein functions. We describe the properties of OPDA that are linked to the activities of PGs, which are derived from arachidonic acid and act as tissue hormones in animals, including humans. The similarity of OPDA with bioactive PGs is particularly evident for the most-studied cyclopentenone, PG 15-dPGJ2. In addition to chemical approaches towards 12-OPDA synthesis, bio-organic synthesis strategies for 12-OPDA and analogous substances have recently been established. The resulting availability of OPDA will aid the identification of additional effector proteins, help in elucidating the mechanisms of OPDA sensing and transmission, and will foster the analysis of the physiological responses to OPDA in plants. There is a need to determine the compartmentation and transport of 12-OPDA and its conjugates, over long distances as well as short. It will be important to further study OPDA in animal and human cells, for example with respect to beneficial anti-inflammatory and anti-cancer activities. Cell signaling, OPDA, plant, polyunsaturated fatty acids, prostaglandin, synthesis Introduction 12-OPDA was first synthesized and described by Zimmerman and Feng (1978), who concluded that the cyclopentenone ring structure of this acid was analogous to that of the A-type or J-type prostaglandins (PGs) produced in mammalian systems (Fig. 1). The authors created the trivial name oxo-phyto-dienoic-acid (OPDA), with dienoic referring to the carboxylic acid derivative of a hydrocarbon system containing two carbon double-bonds. In addition, they raised the question as to whether 12-OPDA possesses any of the physiological effects of mammalian PGs, such as those related to wound healing (reviewed by Michalik and Wahli, 2006). The physiological role of 12-OPDA as a wound hormone in plants was established by Vick and Zimmerman (1987), Farmer and Ryan (1992), and Stintzi et al. (2001). Another physiological analogy between mammalian cyclopentenone PGs (cyPGs) and 12-OPDA applies to their importance in regulation of reproductive systems. cyPGs play a role, for example, in labor contractions, and 12-OPDA participates in regulating seed dormancy, germination, and embryogenesis (Goetz et al., 2012; Sykes et al., 2012; Dave et al., 2016). The mutual stimulation of research on the connection between 12-OPDA and PGs is perhaps best exemplified by Mats Hamberg who, together with the Nobel Laureate Bengt Samuelsson, isolated the first naturally occurring arachidonic acid (ARA)-derived cyclopentenones in 1966 (Hamberg and Samuelsson, 1966) and who later made important discoveries in 12-OPDA research. It was established that biologically formed 12-OPDA is cis-(+)-12-OPDA. Allene oxide cyclase was identified as the enzyme being responsible for the formation of enantiomerically pure cis-(+)-12-OPDA (Hamberg, 1988; Hamberg et al., 1988). Further similarities between cis-(+)-12-OPDA and biosynthesized cyclopentenones as well as other Michael acceptors (α, β-unsaturated carbonyl compounds) on a biochemical, chemical, gene- and protein-regulatory level are reviewed below. Fig. 1. View largeDownload slide Biosynthesis routes of 12-OPDA and its analogues in humans and plants. Enzymes: COX-2, cyclooxygenase 2; PGDS, prostaglandin D synthase; LOX, lipoxygenase; AOS, allene oxide-synthase; AOC, allene oxide-cyclase; OPR3, oxophytodienoic acid reductase 3. Substrates, intermediates, and products: α-LeA, linolenic acid; 13-HPOT, 13S,9Z,11E,15Z-13-hydroperoxy-9,11,15-octadecatrienoic acid; 12, 13-EOT, 12,13S-epoxy-9Z,11,15Z-octadecatrienoic acid; PPA-1, phytoprostane A1; JA, jasmonic acid; ARA, arachidonic acid; PGH2, prostaglandin H2; PGD2, prostaglandin D2; 15-dPGJ2, 15-deoxy-Prostaglandin J2; 15J2t-IsoP, isoprostane. Fig. 1. View largeDownload slide Biosynthesis routes of 12-OPDA and its analogues in humans and plants. Enzymes: COX-2, cyclooxygenase 2; PGDS, prostaglandin D synthase; LOX, lipoxygenase; AOS, allene oxide-synthase; AOC, allene oxide-cyclase; OPR3, oxophytodienoic acid reductase 3. Substrates, intermediates, and products: α-LeA, linolenic acid; 13-HPOT, 13S,9Z,11E,15Z-13-hydroperoxy-9,11,15-octadecatrienoic acid; 12, 13-EOT, 12,13S-epoxy-9Z,11,15Z-octadecatrienoic acid; PPA-1, phytoprostane A1; JA, jasmonic acid; ARA, arachidonic acid; PGH2, prostaglandin H2; PGD2, prostaglandin D2; 15-dPGJ2, 15-deoxy-Prostaglandin J2; 15J2t-IsoP, isoprostane. The biochemistry of 12-OPDA Biochemical formation of the cyclopentenones 12-OPDA and prostaglandins Cyclopentenone-containing compounds are synthesized by consecutive oxidation, cyclization, and hydrolysis at lipid-derived molecules. The generation of OPDA begins with the lipoxygenase (LOX)-catalysed oxidation of the C18 polyunsaturated fatty acid (PUFA) α-linolenic acid (α-LeA). The hydroperoxylipid that is produced enzymatically forms an epoxide through the action of allene oxide synthase (AOS), and finally is cyclized by allene oxide cyclase (AOC) to form OPDA. OPDA can be further metabolized to jasmonic acid (Fig. 1) (Vick and Zimmerman, 1986; Schaller et al., 2000; Chini et al., 2018). The sequential biosynthesis of OPDA occurs in the chloroplast and is activated by lipases that liberate α-LeA from membrane-embedded glycerolipids such as monogalactosyldiacylglycerol (MGDG). Stress conditions such as the presence of reactive oxygen species (ROS), leaf wounding, or the hypersensitive response stimulate its synthesis. For the wounding-induced stimulus, signal transmission is suggested to propagate to membranes via conserved plant elicitor peptides, such as systemin in tomato or AtPeps in Arabidopsis, leading to lipase-mediated liberation of α-LeA (see Ryan and Pearce, 1998, Huffaker et al., 2013; Klauser et al., 2015). Recent studies have emphasized the importance of abscisic acid (ABA) and the lipase PLIP2 in the case of membrane lipid-derived free 12-OPDA synthesis (Wang et al., 2018). 12-OPDA also occurs as esters with complex lipids, and these so-called Arabidopsides (Stelmach et al., 2001) also depend on the 12-OPDA enzyme trio of LOX, AOS, and AOC. They are suggested to function as an OPDA storage pool (Kourtchenko et al., 2007; Ibrahim et al., 2011). Whether they are formed by esterification of free OPDA with membrane lipids via the action of one or more acyl transferases, or by direct formation on the fatty acyl groups of glycerolipids is a matter of debate (Koo, 2018). Among dicots and monocots, Arabidopsis chloroplasts serve as the richest source of OPDA (~1000 ng g–1 FW). Other valuable sources of OPDA are Zea mays (400–500 ng g–1 FW), Hordeum vulgare (~600 ng g–1 FW), and Arabidopsis seeds (50–60 ng g–1 FW) (Stelmach et al., 1998; Dave et al., 2011; Christensen et al., 2015). Studies in Arabidopsis regarding concentrations of Arabidopsides have revealed that basal levels are between 0.001–0.023 nmol mg–1 DW, with concentrations increasing 200–1000-fold after wounding (Buseman et al., 2006). The esterified forms occur at levels 149-fold greater than those of free cyclopentenones in Arabidopsis (Ibrahim et al., 2011). In humans, cellular synthesis of the five-carbon ring begins with ARA, a C20 PUFA. A prominent cellular product of ARA is the cyclopentanone PGD2, which is highly abundant in hepatocytes (Fukushima, 1992) and mast cells (Scher and Pillinger, 2005). Concentrations of 15-dPGJ2, the PGD2-derived cyPG, range between pico- to nanomolar in human cells. This is sufficient to mediate its anti-inflammatory effects (Kobayashi et al., 2005). As shown in Fig. 1, cyclooxygenases (COXs) and PG synthases such as COX-2 (4COX in the Protein Data Bank, PDB; https://www.rcsb.org) and the prostaglandin synthase PGDS (PDB: 1IYH) sequentially form PGs from ARA. The last step in cyPG biosynthesis is achieved non-enzymatically. Similar to Arabidopsides, esterified cyPGs are found in humans (Gao et al., 2003; Lu et al., 2017, and references therein). While esterified cyclopentanones are present in mammals, jasmonate lipid conjugates have not yet been detected. It is also important to take the distinct subcellular compartmentation and the physico-chemical characteristics of phospholipids and galactolipids into consideration. Generation of cyclopentenones also can occur non-enzymatically, by a free radical-catalysed chemical mechanism starting from PUFAs (Galano et al., 2017). Whether the synthesis of these so-called isoprostanes (in mammalian tissues from ARA, Fig. 1), neuroprostanes (in brain tissues from docosahexaenoic acid), and phytoprostanes (in chloroplasts; see Fig. 1) occurs in a controlled manner is a matter of debate. In plants it is known that phytoprostanes play important roles in regulating sets of genes distinct from their enzymatically derived analogues (Loeffler et al., 2005). It is notable that the basal concentration of phytoprostanes in tomato is higher compared to 12-OPDA, while similar concentration ranges are reported for both oxylipins in Arabidopsis (see Thoma et al., 2003; Mueller, 2004). Regulation of the 12-OPDA synthesis pathway OPDA biosynthesis is induced upon abiotic and biotic stress. Regulation of OPDA synthesis is poorly understood, and the regulatory complexity is further increased by hormonal cross-talk (see below). New approaches are needed to address the regulation of OPDA synthesis. Hofmann et al. (2006) stated that ‘the extremely short half-life of allene oxides and the optical purity of natural 12-OPDA suggest a tight coupling of AOS and AOC’. Channeling of OPDA precursors through supramolecular complexes may explain the efficiency of OPDA synthesis despite the instability of 12, 13S-epoxy-9Z, 11E, 15Z-octadecatrienoic acid (12, 13 EOT), which exists for <20 s at 0 °C, pH 7.4 (Brash et al., 1988), and the thermodynamically preferred conformer of trans-12-OPDA. The metabolic scenario is supported by the occurrence of a LOX–AOS fusion protein in corals (O16025; PDB: 3DY5). In addition, the co-occurrence of LOX-hydroperoxide lyase (HPL) has also been discovered recently in corals (Teder et al., 2017). Various pathways of 13(s)-hydroperoxy-(9Z,11E,15Z)-octadecatrienoic acid (13-HPOT) and 12, 13 EOT metabolism co-exist within the OPDA pathway, providing tentative support for the hypothetical channeling of oxylipin in the chloroplast (Koljak et al., 1997). To date, structural evidence is lacking for an interaction between the four annotated 13-LOX with AOS (PDB: 2RCL) or with HPL (no crystal structure available), as it also is in the case for AOS with AOC (PDB: 2BRJ) (Zerbe et al., 2007). Apart from the possibility of metabolite channeling, rate-limiting steps in oxylipin metabolism can be analysed by studying reaction kinetics and thermodynamics. Tools such as the eQuilibrator (http://equilibrator.weizmann.ac.il/) or Gibbs free energy calculations based on group contribution methods can provide the first clues regarding thermodynamic constraints. The Gibbs formation enthalpy of 12-OPDA is strongly exergonic at –98 kcal mol–1 (Audran et al., 2014) and is similar to that of 13-HPOT when entering the HPL pathway that yields green-leaf volatiles (–90 kcal mol–1), as calculated via the group contribution method by Jankowski et al. (2008). Heteromerization of oxylipin enzymes as shown for AOC in Arabidopsis (Otto et al., 2016), differential subcellular localization of oxylipin enzymes such as AOS and HPL in potato (Farmaki et al., 2007), or the involvement of insect-derived elicitors in suppressing the wound-responsive HPL pathway (Savchenko et al., 2013) have been suggested to participate in regulating oxylipin synthesis. Proteins that activate or repress transcription of 12-OPDA enzymes have recently been compiled by Wasternack and Song (2017). Additional regulation of oxylipin synthesis may involve post-translational modifications (PTMs). The database PhosPhAt (Heazlewood et al., 2008; http://phosphat.uni-hohenheim.de/) reports serine (S) and tyrosine (Y) side-chains of LOX2, LOX6, AOS, and AOC2 as targets of phosphorylation (p). The function of the phosphosites (LOX2: Sp488; LOX6: Sp787, Yp860, Sp865; AOS: Sp34, Sp36, Sp49; AOC2: Sp96) awaits clarification. Table 1 summarizes half-life-times and concentrations of oxylipin enzymes in A. thaliana (Wang et al., 2012; Li et al., 2017). The order of stability is LOX2>AOC2>AOS and the order of abundancies, LOX2>AOS>AOC2, suggest that 13-HPOT-synthesis could be the bottleneck in 12-OPDA synthesis. In O. sativa the amount of free α-LeA is rate-limiting for OPDA synthesis (Christeller and Galis, 2014). Nilsson et al. (2012) found that OPDA is formed from fatty acids that are still esterified to galactolipids after tissue disruption in Arabidopsis. This contradicts the hypothesis of Kourtchenko et al. (2007), who suggested the release of unsaturated fatty acids prior to oxylipin synthesis. Prominent free α-LeA-generating lipases possibly involved in 12-OPDA synthesis are DEFECTIVE IN ANTHER DEHISCENCE1 (DAD 1), diacylglycerol lipase (DGL), and PLASTID LIPASE1 (PLIP1) (Ellinger et al., 2010; Wang et al., 2018). It is likely that there is not a single enzyme but instead several redundant lipases that participate in the release of α-LeA. Fungal lipases efficiently hydrolyse Arabidopsides (Stelmach et al., 2001); however, Buseman et al. (2006) subsequently suggested that the importance of pathogenesis-related lipases proposed by Stelmach et al. (2001) is relative, since they found that mechanical wounding was the most efficient stimulus for 12-OPDA release from Arabidopsides. Table 1. Abundance and stability of 12-OPDA synthesis enzymes or other oxylipin enzymes in Arabidopsis Enzyme KD (d–1) Protein abundance (ppm) Whole organism Leaf LOX 1 n.a. 76.6 6.12 LOX 2 0.180i 921 2304 LOX 3 n.a. 0.36 6.69 LOX 4 n.a. 0.45 3.77 LOX 5 n.a. 2.22 n.a. LOX 6 n.a. 7.66 0.73 AOS 0.523f 1265 178 AOC 1 0.238f 21.2 38 AOC 2 0.257f 44.3 114 AOC 3 n.a. 42 6.59 AOC 4 0.114i 115 58 DOX 1 n.a. 91.2 0.22 DOX 2 n.a. n.a. n.a. HPL 1 n.a. 0.01 n.a. Enzyme KD (d–1) Protein abundance (ppm) Whole organism Leaf LOX 1 n.a. 76.6 6.12 LOX 2 0.180i 921 2304 LOX 3 n.a. 0.36 6.69 LOX 4 n.a. 0.45 3.77 LOX 5 n.a. 2.22 n.a. LOX 6 n.a. 7.66 0.73 AOS 0.523f 1265 178 AOC 1 0.238f 21.2 38 AOC 2 0.257f 44.3 114 AOC 3 n.a. 42 6.59 AOC 4 0.114i 115 58 DOX 1 n.a. 91.2 0.22 DOX 2 n.a. n.a. n.a. HPL 1 n.a. 0.01 n.a. KD, mean degradation rate: f, fast, i, intermediate, n.a., information not available. Data are taken from Li et al. (2017). Protein abundance is taken from the database PaxDb (https://pax-db.org/). Protein abundance values are expressed as parts per million (ppm) relative to the entire proteome (Wang et al., 2012) View Large Table 1. Abundance and stability of 12-OPDA synthesis enzymes or other oxylipin enzymes in Arabidopsis Enzyme KD (d–1) Protein abundance (ppm) Whole organism Leaf LOX 1 n.a. 76.6 6.12 LOX 2 0.180i 921 2304 LOX 3 n.a. 0.36 6.69 LOX 4 n.a. 0.45 3.77 LOX 5 n.a. 2.22 n.a. LOX 6 n.a. 7.66 0.73 AOS 0.523f 1265 178 AOC 1 0.238f 21.2 38 AOC 2 0.257f 44.3 114 AOC 3 n.a. 42 6.59 AOC 4 0.114i 115 58 DOX 1 n.a. 91.2 0.22 DOX 2 n.a. n.a. n.a. HPL 1 n.a. 0.01 n.a. Enzyme KD (d–1) Protein abundance (ppm) Whole organism Leaf LOX 1 n.a. 76.6 6.12 LOX 2 0.180i 921 2304 LOX 3 n.a. 0.36 6.69 LOX 4 n.a. 0.45 3.77 LOX 5 n.a. 2.22 n.a. LOX 6 n.a. 7.66 0.73 AOS 0.523f 1265 178 AOC 1 0.238f 21.2 38 AOC 2 0.257f 44.3 114 AOC 3 n.a. 42 6.59 AOC 4 0.114i 115 58 DOX 1 n.a. 91.2 0.22 DOX 2 n.a. n.a. n.a. HPL 1 n.a. 0.01 n.a. KD, mean degradation rate: f, fast, i, intermediate, n.a., information not available. Data are taken from Li et al. (2017). Protein abundance is taken from the database PaxDb (https://pax-db.org/). Protein abundance values are expressed as parts per million (ppm) relative to the entire proteome (Wang et al., 2012) View Large Regulatory roles of cyclopentenones in transcription and translation In nature, organisms are often challenged by varying environmental conditions such as extreme temperatures, wounding, and exposure to toxins or pathogens. A common hallmark of these stresses is the enhanced synthesis of reactive oxygen and nitrogen species (ROS, RNS) and the development of redox imbalances. Thus, successful stress acclimation depends on redox homeostasis and maintenance of a reducing environment, with glutathione redox potentials more negative than –300 mV; glutathione (GSH) being the major redox thiol buffer of the cell. Redox homeostasis depends on a thiol network comprised of redox transmitters, regulated targets, and sensors such as peroxiredoxins (König et al., 2012). As oxidized derivatives of lipids, cyclopentenones carry information about the redox status of the cell. Hence, accumulation of OPDA and cyPGs may be considered as ideal candidate signals to modulate antioxidant gene expression. Indeed, in mammals adjustment is achieved by inducing GSH synthesis genes through 15-dPGJ2 (Levonen et al., 2004). A similar scenario has been described in plants where OPDA stimulates GSH synthesis through activation of the cysteine synthase complex (Park et al., 2013). The regulation of GSH synthesis in mammals is mediated by the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-erythroid 2-related factor 2 (Nrf2) complex. Keap1 is a redox sensor that, under normal conditions, acts as a negative regulator of the transcription factor Nrf2. Keap1 has highly reactive (low pKa) cysteines that are readily alkylated (cyPGylated) by the Michael acceptor 15-dPGJ2. Upon alkylation of specific Keap1 cysteines, Nrf2 is released from the complex, translocates to the nucleus where it binds to antioxidant responsive elements (AREs), and activates gene expression of antioxidant enzymes such as the GSH synthetic genes glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC) (Levonen et al., 2004; Sihvola and Levonen, 2017). Sequences homologous to the ARE element have so far not been identified in planta. However, OPDA also controls a set of genes independent of jasmonic acid (JA) (Stintzi et al., 2001; Taki et al., 2005; Dave and Graham, 2012). A selective overview of genes regulated by OPDA and mammalian cyPGs is given in Tables 2 and 3. Strikingly, heat-shock proteins, glutathione-S-transferases, calcium-associated proteins, transcription factors, and kinases are targets of both mammalian and plant cyclopentenones. Table 2. Modulation of gene expression by the cyclopentenone prostaglandin 15-dPGJ2. The gene product, its major function, and the direction of transcript response (up- or down-regulated) are indicated. The information is not exhaustive, and other genes are also modulated. Gene product Major function Transcript response Reference Heat-shock protein 70 Heat shock Up Vanaja et al. (2000) Glutathione-S-transferases ROS stress Up Kawamoto et al. (2000) γ-Glutamate cysteine ligase ROS stress Up Levonen et al. (2004) Heme oxygenase ROS stress Up Lim et al. (2007) Peroxiredoxin 1 ROS stress Up Sperandio et al. (2017) Peroxiredoxin 4 ROS stress Up Sperandio et al. (2017) Cyclin D1 Kinase activator Down Campo et al. (2002) Cyclooxygenase COX-2 PG synthesis Up Fahmi et al. (2002) Down Tsubouchi et al. (2001) IKK Phosphorylation Down Rossi et al. (2000) cPLA2 PG synthesis Down Tsubouchi et al. (2001) Gene product Major function Transcript response Reference Heat-shock protein 70 Heat shock Up Vanaja et al. (2000) Glutathione-S-transferases ROS stress Up Kawamoto et al. (2000) γ-Glutamate cysteine ligase ROS stress Up Levonen et al. (2004) Heme oxygenase ROS stress Up Lim et al. (2007) Peroxiredoxin 1 ROS stress Up Sperandio et al. (2017) Peroxiredoxin 4 ROS stress Up Sperandio et al. (2017) Cyclin D1 Kinase activator Down Campo et al. (2002) Cyclooxygenase COX-2 PG synthesis Up Fahmi et al. (2002) Down Tsubouchi et al. (2001) IKK Phosphorylation Down Rossi et al. (2000) cPLA2 PG synthesis Down Tsubouchi et al. (2001) View Large Table 2. Modulation of gene expression by the cyclopentenone prostaglandin 15-dPGJ2. The gene product, its major function, and the direction of transcript response (up- or down-regulated) are indicated. The information is not exhaustive, and other genes are also modulated. Gene product Major function Transcript response Reference Heat-shock protein 70 Heat shock Up Vanaja et al. (2000) Glutathione-S-transferases ROS stress Up Kawamoto et al. (2000) γ-Glutamate cysteine ligase ROS stress Up Levonen et al. (2004) Heme oxygenase ROS stress Up Lim et al. (2007) Peroxiredoxin 1 ROS stress Up Sperandio et al. (2017) Peroxiredoxin 4 ROS stress Up Sperandio et al. (2017) Cyclin D1 Kinase activator Down Campo et al. (2002) Cyclooxygenase COX-2 PG synthesis Up Fahmi et al. (2002) Down Tsubouchi et al. (2001) IKK Phosphorylation Down Rossi et al. (2000) cPLA2 PG synthesis Down Tsubouchi et al. (2001) Gene product Major function Transcript response Reference Heat-shock protein 70 Heat shock Up Vanaja et al. (2000) Glutathione-S-transferases ROS stress Up Kawamoto et al. (2000) γ-Glutamate cysteine ligase ROS stress Up Levonen et al. (2004) Heme oxygenase ROS stress Up Lim et al. (2007) Peroxiredoxin 1 ROS stress Up Sperandio et al. (2017) Peroxiredoxin 4 ROS stress Up Sperandio et al. (2017) Cyclin D1 Kinase activator Down Campo et al. (2002) Cyclooxygenase COX-2 PG synthesis Up Fahmi et al. (2002) Down Tsubouchi et al. (2001) IKK Phosphorylation Down Rossi et al. (2000) cPLA2 PG synthesis Down Tsubouchi et al. (2001) View Large Table 3. Genes regulated by 12-OPDA . A selection of transcripts that are up- or down-regulated by 12-OPDA (Taki et al., 2005) Gene product Gene ID Major function Transcript response ABC transporter At1g15520 Transporter Up Protein kinase At3g25250 Phosphorylation Up Ethylene responsive transcription factor At1g22810 Transcription factor Up C2H2 Zn finger transcription factor At2g37430 Transcription factor Up CML 40 At3g01830 Calcium sensor Up CML 45 At5g39670 Calcium sensor Up HSP At1g53540 Heat shock Up HSP 17.4 At3g46230 Heat shock Up HSP At5g12030 Heat shock Up HSP 17 6a At1g52560 Heat shock Up HSP 70 b At1g16030 Heat shock Up Quercetin glucosyltransferase At2g15480 Genereal stress Up Glutathione-S-transferase 6 At2g47730 ROS stress Up FAD oxidoreductase At1g30700 ROS stress Up Pyridine nucleotide disulphide oxido-reductase At5g22140 ROS stress Up Zn finger protein, SAP 12 At3g28210 ROS stress Up Kinase like protein At4g 23190 Phosphorylation Down Phosphatidylinositol 3- and 4-kinase family At1g64460 Phosphorylation Down Peroxidase, putative At1g05240 ROS stress Down Plasma membrane H+-ATPase like At3g60330 H+-ATPase activity Down Proline-rich protein At3g62680 Root hair formation Down Glycosyl hydrolase family 9 At1g48930 Cell wall organization Down Invertase/pectin methylesterase inhibitor family At5g62340 Enzyme inhibitor Down Gene product Gene ID Major function Transcript response ABC transporter At1g15520 Transporter Up Protein kinase At3g25250 Phosphorylation Up Ethylene responsive transcription factor At1g22810 Transcription factor Up C2H2 Zn finger transcription factor At2g37430 Transcription factor Up CML 40 At3g01830 Calcium sensor Up CML 45 At5g39670 Calcium sensor Up HSP At1g53540 Heat shock Up HSP 17.4 At3g46230 Heat shock Up HSP At5g12030 Heat shock Up HSP 17 6a At1g52560 Heat shock Up HSP 70 b At1g16030 Heat shock Up Quercetin glucosyltransferase At2g15480 Genereal stress Up Glutathione-S-transferase 6 At2g47730 ROS stress Up FAD oxidoreductase At1g30700 ROS stress Up Pyridine nucleotide disulphide oxido-reductase At5g22140 ROS stress Up Zn finger protein, SAP 12 At3g28210 ROS stress Up Kinase like protein At4g 23190 Phosphorylation Down Phosphatidylinositol 3- and 4-kinase family At1g64460 Phosphorylation Down Peroxidase, putative At1g05240 ROS stress Down Plasma membrane H+-ATPase like At3g60330 H+-ATPase activity Down Proline-rich protein At3g62680 Root hair formation Down Glycosyl hydrolase family 9 At1g48930 Cell wall organization Down Invertase/pectin methylesterase inhibitor family At5g62340 Enzyme inhibitor Down View Large Table 3. Genes regulated by 12-OPDA . A selection of transcripts that are up- or down-regulated by 12-OPDA (Taki et al., 2005) Gene product Gene ID Major function Transcript response ABC transporter At1g15520 Transporter Up Protein kinase At3g25250 Phosphorylation Up Ethylene responsive transcription factor At1g22810 Transcription factor Up C2H2 Zn finger transcription factor At2g37430 Transcription factor Up CML 40 At3g01830 Calcium sensor Up CML 45 At5g39670 Calcium sensor Up HSP At1g53540 Heat shock Up HSP 17.4 At3g46230 Heat shock Up HSP At5g12030 Heat shock Up HSP 17 6a At1g52560 Heat shock Up HSP 70 b At1g16030 Heat shock Up Quercetin glucosyltransferase At2g15480 Genereal stress Up Glutathione-S-transferase 6 At2g47730 ROS stress Up FAD oxidoreductase At1g30700 ROS stress Up Pyridine nucleotide disulphide oxido-reductase At5g22140 ROS stress Up Zn finger protein, SAP 12 At3g28210 ROS stress Up Kinase like protein At4g 23190 Phosphorylation Down Phosphatidylinositol 3- and 4-kinase family At1g64460 Phosphorylation Down Peroxidase, putative At1g05240 ROS stress Down Plasma membrane H+-ATPase like At3g60330 H+-ATPase activity Down Proline-rich protein At3g62680 Root hair formation Down Glycosyl hydrolase family 9 At1g48930 Cell wall organization Down Invertase/pectin methylesterase inhibitor family At5g62340 Enzyme inhibitor Down Gene product Gene ID Major function Transcript response ABC transporter At1g15520 Transporter Up Protein kinase At3g25250 Phosphorylation Up Ethylene responsive transcription factor At1g22810 Transcription factor Up C2H2 Zn finger transcription factor At2g37430 Transcription factor Up CML 40 At3g01830 Calcium sensor Up CML 45 At5g39670 Calcium sensor Up HSP At1g53540 Heat shock Up HSP 17.4 At3g46230 Heat shock Up HSP At5g12030 Heat shock Up HSP 17 6a At1g52560 Heat shock Up HSP 70 b At1g16030 Heat shock Up Quercetin glucosyltransferase At2g15480 Genereal stress Up Glutathione-S-transferase 6 At2g47730 ROS stress Up FAD oxidoreductase At1g30700 ROS stress Up Pyridine nucleotide disulphide oxido-reductase At5g22140 ROS stress Up Zn finger protein, SAP 12 At3g28210 ROS stress Up Kinase like protein At4g 23190 Phosphorylation Down Phosphatidylinositol 3- and 4-kinase family At1g64460 Phosphorylation Down Peroxidase, putative At1g05240 ROS stress Down Plasma membrane H+-ATPase like At3g60330 H+-ATPase activity Down Proline-rich protein At3g62680 Root hair formation Down Glycosyl hydrolase family 9 At1g48930 Cell wall organization Down Invertase/pectin methylesterase inhibitor family At5g62340 Enzyme inhibitor Down View Large Proteome analyses have revealed OPDA-regulated chloroplast- and nucleus-encoded gene products in Arabidopsis and the moss Physcomitrella patens (Dueckershoff et al., 2008; Toshima et al., 2014; Luo et al., 2016). The induction of AOC in P. patens and LOX 2 in Arabidopsis by OPDA suggests that OPDA stimulates its own synthesis. In the moss, OPDA suppresses protein synthesis and expression of proteins involved in protein folding, while the opposite trend is observed in Arabidopsis Enzymes involved in carbon fixation, such as Rubisco, glyceraldehyde 3-phosphatase dehydrogenase, phosphoribulokinase, and sedoheptulose-bisphosphatase are inhibited in P. patens when the thalli are supplemented with OPDA. In Arabidopsis, the up-regulation of peroxiredoxins, thioredoxins, glutathione-S-transferases, cyclophilin 20–3 (Cyp20-3), γ-glutamyl cysteine synthetase, and dehydroascorbate reductase (Dueckershoff et al., 2008) underlines the importance of OPDA as a regulator of redox homeostasis, and it is fine-tuned through its communication with a dynamically interacting module consisting of Cyp20-3, O-acetylserine(thiol)lyase B (OASTL-B), 2-cysteine peroxiredoxins A/B (2-CysPrx), and serine acetyltransferase 2;1 (SERAT2;1) (Müller et al., 2017). OPDA up-regulates proteins of the oxygen-evolving complex both in Arabidopsis and P. patens, suggesting a role in the regulation of photosynthesis. Transcriptomics and proteomics of OPDA mutant lines, such as dde2-2 and cpm2 (von Malek et al., 2002; Riemann et al., 2013), and the recent finding that JA can be synthesized independently of OPR3 will help to provide insights into the underlying mechanisms (Chini et al., 2018). It appears that vertebrates employ 15-dPGJ2 and plants OPDA to regulate similar genetic and physiological processes. The precise role of 15-dPGJ2 in redox, ROS, and RNS regulation still needs to be scrutinized. The up-regulation of heme oxygenase (Lim et al., 2007; Table 2) provides additional support for a role of 15-dPGJ2 in re-establishing redox homeostasis: it participates in heme degradation, but also in antioxidant defense (Chau et al., 2015). It would be interesting to study the divergence of C18 and C20 cyclopentenones during evolution and the new functions that emerged in photosynthetic plants, and alga and mosses should be considered in addition to angiosperms. Protein targets of 12-OPDA Two OPDA-interacting proteins have been described, namely Cyp20-3 (Park et al., 2013) and GSTU 19 (Dixon and Edwards, 2009). Thus, in comparison to other plant hormones information regarding protein interactions with OPDA is still scarce. The specificity of ligand–protein interactions is partly due to chemical properties and steric features of the ligand, as demonstrated by comparison of 12-OPDA with iso-OPDA. The rearrangement of the double-bond within the cyclopentenone moiety of 12-OPDA leads to iso-OPDA and affects the structure and reactivity of the molecule. The change of the PG A moiety into the PG B ring abolishes the bioactivity of 12-OPDA (Schulze et al., 2007). As is the case with cyPGs, OPDA is a Michael acceptor. Therefore, it has been proposed that OPDA covalently binds to proteins by forming an ether bridge with cysteine thiols. This process of covalent addition of OPDA to cysteine-containing proteins may be termed OPDAylation. In comparison to OPDA, phytoprostanes such as PPA1 regulate expression of distinct genes and, in analogy to humans, only a subset of cellular proteins is modified by cyclopentenone-containing prostanoids (Thoma et al., 2003; Loeffler et al., 2005; Gayarre et al., 2007; Dueckershoff et al., 2008). Differences in the mode of interactions between cyclopentenone-containing prostanoids and proteins might be due to changes in molecular composition and stereochemistry, and should be taken into account when drawing parallels between cyPGs, phytoprostanes, and 12-OPDA. Table 4 lists putative OPDA targets in plants, as determined by a Blast search querying mammalian proteins with thiols susceptible to cyPGylation (Koharudin et al., 2010; Oeste and Pérez-Sala, 2014) against the Arabidopsis protein database. Table 4. Selection of 15-dpGJ2 target proteins in humans and putative 12-OPDA targets in plants Human protein Target site Similar Arabidopsis protein Putative target site GSTP1-1 P09211 Cys 47 and Cys 101 – – Keap1 Q14145 Cys 273 and Cys 288 Influenza virus binding protein F4K9G6 Cys 338 AP-1 P05412 Cys 269 – – TRX P10599 Cys 35 and Cys 69 Thioredoxin f Q9XFH8 Cys 102 H-Ras P01112 Cys 118, Cys 181 and Cys 184 RABD2c Q9SEH3 Cys 123 NF-κB p50 P19838 Cys 61 – – UCH-L1 Cys 152 UCH 3, Q8GWE1 – Human protein Target site Similar Arabidopsis protein Putative target site GSTP1-1 P09211 Cys 47 and Cys 101 – – Keap1 Q14145 Cys 273 and Cys 288 Influenza virus binding protein F4K9G6 Cys 338 AP-1 P05412 Cys 269 – – TRX P10599 Cys 35 and Cys 69 Thioredoxin f Q9XFH8 Cys 102 H-Ras P01112 Cys 118, Cys 181 and Cys 184 RABD2c Q9SEH3 Cys 123 NF-κB p50 P19838 Cys 61 – – UCH-L1 Cys 152 UCH 3, Q8GWE1 – Human 15-dpGJ2 target proteins are taken from Oeste and Pérez-Sala (2014), and for UCH-L1 from Koharudin et al. (2010), and aligned against the A. thaliana protein database. Identification of potential 12-OPDA targets is based on sequence similarities and conservation of the involved Cys residues. For additional information on the proteins see the respective entries in Uniprot (https://www.uniprot.org). View Large Table 4. Selection of 15-dpGJ2 target proteins in humans and putative 12-OPDA targets in plants Human protein Target site Similar Arabidopsis protein Putative target site GSTP1-1 P09211 Cys 47 and Cys 101 – – Keap1 Q14145 Cys 273 and Cys 288 Influenza virus binding protein F4K9G6 Cys 338 AP-1 P05412 Cys 269 – – TRX P10599 Cys 35 and Cys 69 Thioredoxin f Q9XFH8 Cys 102 H-Ras P01112 Cys 118, Cys 181 and Cys 184 RABD2c Q9SEH3 Cys 123 NF-κB p50 P19838 Cys 61 – – UCH-L1 Cys 152 UCH 3, Q8GWE1 – Human protein Target site Similar Arabidopsis protein Putative target site GSTP1-1 P09211 Cys 47 and Cys 101 – – Keap1 Q14145 Cys 273 and Cys 288 Influenza virus binding protein F4K9G6 Cys 338 AP-1 P05412 Cys 269 – – TRX P10599 Cys 35 and Cys 69 Thioredoxin f Q9XFH8 Cys 102 H-Ras P01112 Cys 118, Cys 181 and Cys 184 RABD2c Q9SEH3 Cys 123 NF-κB p50 P19838 Cys 61 – – UCH-L1 Cys 152 UCH 3, Q8GWE1 – Human 15-dpGJ2 target proteins are taken from Oeste and Pérez-Sala (2014), and for UCH-L1 from Koharudin et al. (2010), and aligned against the A. thaliana protein database. Identification of potential 12-OPDA targets is based on sequence similarities and conservation of the involved Cys residues. For additional information on the proteins see the respective entries in Uniprot (https://www.uniprot.org). View Large Conjugates of OPDA with cellular redox buffers and chemical modulation of OPDA bioactivity Plants rely on two soluble redox buffers consisting of the glutathione pool (GSH and diglutathionyldisulfide, GSSG) and the ascorbate pool (ascorbate, Asc; monodehydroasorbate, MDA; (di)dehydroascorbate, DHA). Cyclopentenone reacts with both GSH and Asc (phosphate buffer, neutral pH; D. Maynard et al., unpublished results) and we are currently investigating how the side-chain moieties and their configurations affect the reactivity of cyclopentenones with both redox buffers. In vitro OPDA reacts with GSH enzymatically and spontaneously (Dueckershoff et al., 2008). GSH is essential for regeneration of Asc from dehydroascorbate (Wang and Ballatori, 1998), and this is intriguing since OPDA up-regulates dehydroascorbate reductase, glutathione S-transferase, and γ-glutamylcysteinyl synthase (γ-ECS), the latter catalysing the committed step of GSH synthesis (Dueckershoff et al., 2008; Park et al., 2013). As described above, OPDA stimulates synthesis of GSH by binding to Cyp20-3 and activating the chloroplast cysteine synthase complex (Park et al., 2013). For the time being it may be assumed that OPDA contributes to regulating the redox buffers GSH and Asc in vivo. Likewise, few studies have addressed the role of GSH in regulating the bioactivity of OPDA. The OPDA-GSH conjugate exists in planta (Fig. 2) and it has been found to be transported into the vacuole for degradation (Ohkama-Ohtsu et al., 2011). Conjugate formation between OPDA and GSH may allow for fine-tuning or modulation of OPDA bioactivity. Regulation of genes independent of OPDA have been reported for the 12-OPDA-Ile adduct (Fig. 2) (Arnold et al., 2016), but comparative transcriptome analyses for transcripts responsive to OPDA and OPDA-GSH conjugate are lacking. Inactivation of OPDA through enzymatic conjugation with GSH and successive deglutathionylation has been reported in the gut of insects (Dąbrowska et al., 2009). The cis-iso isomerization of the double-bond, which leads to planarization of the substituted cyclopentenone, has also been reported in humans for PG A1 (Davis and Horton, 1972; Monkhous et al., 1973). OPDA and iso-12-OPDA (Fig. 2) feed into JA and cis-JA synthesis, with distinct functions (Dąbrowska and Boland, 2007; Matthes et al., 2010; Matsui et al., 2017). Support for a role of iso-12-OPDA as a bioactive molecule distinct from 12-OPDA is found in a study by Loeffler et al. (2005) that shows that an iso-12-OPDA analogue functions in plant defense and detoxification responses. There is a need to explore the structure–function relationships of cyclopentenones with variations in chain length, number of double-bonds, bond configuration, and number of hydroxyl moieties (Bui and Straus, 1998; Blechert et al., 1999; Costabile et al., 2017). Fig. 2. View largeDownload slide Chemical structures of 12-OPDA-derived plant molecules other than jasmonic acid. (A) Iso-12-OPDA, (B) 12-OPDA-GSH, (C) cis-Jasmone, and (D) 12-OPDA-Ile. Fig. 2. View largeDownload slide Chemical structures of 12-OPDA-derived plant molecules other than jasmonic acid. (A) Iso-12-OPDA, (B) 12-OPDA-GSH, (C) cis-Jasmone, and (D) 12-OPDA-Ile. 12-OPDA interactions with plant signaling molecules 12-OPDA is involved in a multitude of plant responses and plant developmental processes. Current knowledge regarding its cross-talk with other phythohormones/signaling molecules has been reviewed by Wasternack (2015) and Per et al. (2018). Here, we consider the interactions with salicylic acid (SA), abscisic acid (ABA), and nitric oxide (NO). 12-OPDA and salicylic acid The chorismate-derived aromatic compound 2-hydroxybenzoic acid (SA) is essential in plant defense (Loake and Grant, 2007). SA affects the human PG and plant OPDA biosynthesis pathways, indicating similar ligand–enzyme interactions irrespective of origin. SA decreases the expression of the OPDA biosynthetic enzymes LOX2, AOC2, and AOS in Arabidopsis (Leon-Reyes et al., 2010), inhibits lipoxygenase activities in soybean and pea (Yan et al., 2008; Lapenna et al., 2009), and it affects the activity of AOS. SA stimulates the α-dioxygenase (α-DOX)-dependent oxylipin pathway in Arabidopsis, which supports the proposed antagonism between OPDA and SA signaling (De León et al., 2002); however, SA stimulation of α-DOX is not observed in rice. The cross-talk between SA and oxylipin synthesis remains controversial: SA has a positive effect on AOS activity in Arabidopsis (Laudert and Weiler, 1998; Koeduka et al., 2005) but a repressive effect on AOS in flax, rubber tree (Harms et al., 1998; Norton et al., 2007), pea (Yan et al., 2008), and tomato (Sivasankar et al., 2000). Overall, the available data suggest that regulation of the oxylipin pathways by SA differs among plant species. 12-OPDA and abscisic acid Abscisic acid is an important phytohormone that shares striking similarities with OPDA. Both ABA and OPDA are involved in defense responses to pathogens (Stintzi et al., 2001; Lievens et al., 2017), induce stomatal closure (Savchenko et al., 2014), influence metabolism and redox homeostasis (Taki et al., 2005; Ghassemian et al., 2008; Krasensky and Jonak, 2012; Park et al., 2013; Luo et al., 2016), and play a role in plant cell differentiation and morphogenesis (Cheng et al., 2014; Enomoto et al., 2017). On a chemical level, both covalently interact with cysteine (D. Maynard et al., unpublished results). Apart from the established ABA receptors, the affinity of thiols to ABA and OPDA should also be considered as a possible mode of action. The latest breakthrough in the study of hormone cross-talk for both acids has been the observation that ABA affects 12-OPDA concentration (Wang et al., 2018). 12-OPDA and NO NO modulates stress responses in plants, and may affect the precursor pool of α-LeA needed for 12-OPDA synthesis by forming nitrated α-LeA (NO2-LeA). NO2-LeA has signaling functions and induces genes involved in stress regulation, such as those coding HSPs that are also regulated by 12-OPDA (Taki et al., 2005; Mata-Pérez et al., 2016). Application of NO decreases AOC transcript levels but increases those of LOX3, OPR-1, 2, and 3 (Schaller et al., 2000; Chini et al., 2018; Per et al., 2018). An antagonistic relationship was demonstrated by Sun et al. (2017), who showed that NO-scavenging enzymes are up-regulated by 12-OPDA in chloroplast-free leaf sections of variegated Epipremnum aureum that are devoid of ROS-scavenging flavonoids. Interestingly, the physiological response is similar if 12-OPDA is supplied to mammalian cells. Thus, 12-OPDA reduces cellular NO amounts (Taki-Nakano et al., 2016), indicating the existence of similar signal transduction pathways or evolutionary convergence of the response to administered cyclopentenones in animals and plants. The synthesis of 12-OPDA The need for 12-OPDA synthesis, its demands and routes OPDA is involved in heat-shock regulation (Muench et al., 2016), control of stomatal conductance (Meza-Canales et al., 2017), seed dormancy and germination (Dave et al., 2016), and rapid acclimation to high light intensity (Alsharafa et al., 2014). Furthermore, the isoleucine adduct of 12-OPDA has bioactivity independent of OPDA (Arnold et al., 2016). Bio-medicinal studies have determined that OPDA inhibits proliferation of breast cancer cells (Altiok et al., 2008), attenuates lipopolysaccharide-induced inflammation in mouse brain cells (Taki-Nakano et al., 2016), and suppresses H2O2-induced cytotoxicity in human neuroblastoma cells (Taki-Nakano et al., 2014). In comparison to PGs, and also to well-known phytohormones such as SA, ABA, and indole acetic acid (IAA), investigations on medicinal applications of 12-OPDA are in their infancy, probably due to the high cost of OPDA and consequently less research on this topic. Publication numbers may serve as an indication for the need to develop the field of OPDA research; during the last 40 years since its discovery, publications mentioning oxo-phytodienoic acid in their title have numbered less than 100 whereas in contrast 9300 articles have dealt with ABA, 11 500 with SA, and 3150 with IAA (data from Google Scholar). For both plant and human research, it is of interest to synthesize the compound in a relatively easy, cost- and time-efficient way. From a chemist’s point of view, it has been a challenging task to synthesize such an enantiomerically pure cyclopentenone derivative with two stereogenic centers, as well as related derivatives. The first organic synthesis of 12-OPDA was described by Crombie and Mistry (1988) 10 years after its discovery, using cis-cyclopentenediacetic acid as the starting material. This multi-step synthesis produces the desired 12-OPDA in racemic form (Crombie and Mistry, 1988, 1991). One year later the synthesis of the ‘extremely sensitive cyclopentenone’ in enantiomerically pure form was accomplished by a Lewis acid-catalysed retro-Diels–Alder reaction of a chiral norbornene derivative with methylaluminium dichloride (Grieco and Abood, 1989). This substrate for the retro-Diels–Alder reaction was obtained through diastereoselective derivatizations of an enantiomerically pure tricyclodecadienone as the starting material (Fig. 3, Route A). Key steps are two initial alkylation reactions as well as the final ‘release’ of the protected C=C double-bond through a retro-Diels–Alder reaction. Fig. 3. View largeDownload slide Overview of methods for synthesis of 12-OPDA via chemical total synthesis. The three routes are discussed in detail in the text. Fig. 3. View largeDownload slide Overview of methods for synthesis of 12-OPDA via chemical total synthesis. The three routes are discussed in detail in the text. Another successful stereoselective chemical total synthesis of 12-OPDA was demonstrated by the Kobayashi group, starting from a suitable substituted cyclopent-2-enol enantiomer (Kobayashi and Matsuumi, 2002; Ainai et al., 2003; Nonaka et al., 2010). This starting material is readily accessible from (1R)-cyclopent-en-1, 4-diol monoacetate, which can be efficiently prepared through lipase-catalysed desymmetrization with >99% enantiomeric excess (Nonaka et al. 2010). The total synthesis towards 12-OPDA then comprises (among other steps) an allylic substitution, an iodolactonization, and a Wittig reaction (Fig. 3, Route B; Nonaka et al. 2010). An enantioselective route towards 12-OPDA based on an asymmetric allylic substitution that utilizes a chiral palladium catalyst as a key step was reported by the Helmchen group (Fig. 3, Route C; Ernst and Helmchen, 2002). Starting from prochiral cyclopenten-2-yl chloride, this chemocatalytic transformation gives a chiral cyclopentenyl-substituted malonate, which is then further transformed within a diastereoselective synthesis towards (+)-OPDA. It is notable that all of the chemical syntheses shown in Fig. 3 start from a cyclic, heteroatom-substituted cyclopentene moiety, followed by tailor-made alkylation and introduction of the side-chains, whereas in nature the biosynthetic route is based on a cyclization reaction starting from the linear substrate linolenic acid, which already contains all the carbon atoms required in 12-OPDA in the substrate. The recent publication by Uchiyama et al. (2018) of a method for 12-OPDA-Ile synthesis demonstrated that an amino acid–PUFA conjugate can also serve as source for in vitro and in vivo cyclopentenone synthesis. The first efforts towards synthesizing 12-OPDA from natural sources using a multi-enzymatic ‘one-pot’ approach were made by Zerbe et al. (2007), Kajiwara et al. (2012), Le et al. (2017), and Maynard et al. (2018) (see Table 5 for OPDA synthesis strategies). A current challenge is to scale up such small-scale bio-organic approaches in order to develop a large-scale process for the synthesis of 12-OPDA. Table 5. 12-OPDA synthesis routes Method 12-OPDA yield Reference α-LeA + flaxseed extract nd Zimmerman and Feng (1978) α-LeA + SLOX + AOS + crude potato AOC 10% (+)-cis 98:2 cis:trans Laudert et al. (1997) α-LeA + SLOX + Ni-NTA immobilized enzyme duo-AOS-AOC2 20% (+)-cis >95:<5 cis:trans Zerbe et al. (2007) α-LeA + flaxseed extract + Pp-AOC 2 39% (+)-cis >95:<5 cis:trans Kajiwara et al. (2012) α-LeA + rice husk silica immobilized enzyme triade-SLOX- Os-AOS-Os-AOC 65.1–83.6% Le et al. (2017) α-LeA + LOX 6 + AOS + AOC2 13% (+)-cis 98:2 cis:trans Maynard et al. (2018) Method 12-OPDA yield Reference α-LeA + flaxseed extract nd Zimmerman and Feng (1978) α-LeA + SLOX + AOS + crude potato AOC 10% (+)-cis 98:2 cis:trans Laudert et al. (1997) α-LeA + SLOX + Ni-NTA immobilized enzyme duo-AOS-AOC2 20% (+)-cis >95:<5 cis:trans Zerbe et al. (2007) α-LeA + flaxseed extract + Pp-AOC 2 39% (+)-cis >95:<5 cis:trans Kajiwara et al. (2012) α-LeA + rice husk silica immobilized enzyme triade-SLOX- Os-AOS-Os-AOC 65.1–83.6% Le et al. (2017) α-LeA + LOX 6 + AOS + AOC2 13% (+)-cis 98:2 cis:trans Maynard et al. (2018) Unless indicated otherwise, the enzymes are from A. thaliana. nd, not determined. View Large Table 5. 12-OPDA synthesis routes Method 12-OPDA yield Reference α-LeA + flaxseed extract nd Zimmerman and Feng (1978) α-LeA + SLOX + AOS + crude potato AOC 10% (+)-cis 98:2 cis:trans Laudert et al. (1997) α-LeA + SLOX + Ni-NTA immobilized enzyme duo-AOS-AOC2 20% (+)-cis >95:<5 cis:trans Zerbe et al. (2007) α-LeA + flaxseed extract + Pp-AOC 2 39% (+)-cis >95:<5 cis:trans Kajiwara et al. (2012) α-LeA + rice husk silica immobilized enzyme triade-SLOX- Os-AOS-Os-AOC 65.1–83.6% Le et al. (2017) α-LeA + LOX 6 + AOS + AOC2 13% (+)-cis 98:2 cis:trans Maynard et al. (2018) Method 12-OPDA yield Reference α-LeA + flaxseed extract nd Zimmerman and Feng (1978) α-LeA + SLOX + AOS + crude potato AOC 10% (+)-cis 98:2 cis:trans Laudert et al. (1997) α-LeA + SLOX + Ni-NTA immobilized enzyme duo-AOS-AOC2 20% (+)-cis >95:<5 cis:trans Zerbe et al. (2007) α-LeA + flaxseed extract + Pp-AOC 2 39% (+)-cis >95:<5 cis:trans Kajiwara et al. (2012) α-LeA + rice husk silica immobilized enzyme triade-SLOX- Os-AOS-Os-AOC 65.1–83.6% Le et al. (2017) α-LeA + LOX 6 + AOS + AOC2 13% (+)-cis 98:2 cis:trans Maynard et al. (2018) Unless indicated otherwise, the enzymes are from A. thaliana. nd, not determined. View Large 12-OPDA homologues and their synthesis In nature, cyclopentenones are predominantly derived from the PUFAs all-cis-7,10,13-hexadecatrienoic acid, α-LA, α-LeA, ARA, eicosapentaenoic acid (EPA), or DHA. As described for maize, α-linoleic acid can be converted to 10-OPDA in a 9-LOX dependent manner (Fig. 4); 10-OPDA belongs to the ‘death acids’, which accumulate in senescing and necrotic tissue (Christensen et al., 2015). Dinor-oxo-phytodienoic acid (dn-OPDA, Fig. 4) was first described in Arabidopsis and Capsicum annuum (Weber et al., 1997). A highly informative paper concerning lipid contents and the evolution of 16:3- and 18:3-containing plants was published by Mongrand et al. (1998). It is still debated whether dn-OPDA is ubiquitous amongst plants, independent of the content of 16:3 PUFAs but dependent on that of 18:3 PUFAs. A recent study has suggested that dn-OPDA is synthesized independently of 16:3 PUFA content through a single round of ß-oxidation of 12-OPDA (Chini et al., 2018). Synthesis of cyclopentenones such as OPDA, (4Z,7Z,10Z)-12-[[-(1S,5S)-4-oxo-5-(2Z)-pent-2-en-1yl]-cyclopent-2-en-1yl] dodeca-4,7,10-trienoic acid (OCPD) (Fig. 4) and others mentioned by Ziegler et al. (1999) can be achieved by introducing the respective ω-3 derivatives (for synthesis of PUFAs see Durand et al., 2000) that contain at least three cis double-bonds arranged in the order ω-3, ω-6, and ω-9 into the one-pot cascade described by Maynard et al. (2018). Following this approach, it is envisioned that JA, the derivative of 12-OPDA (Fig. 1), could be produced by introducing all-cis-dodecatrienoic acid (synthesis described in Kodama et al., 1993) into the afore-mentioned one pot strategies, followed by reduction with OPDA reductase (OPR3). Fig. 4. View largeDownload slide Chemical structures of several 12-OPDA homologues. (A) Chromomoric acid C-1, (B) 10-OPDA, (C) dicranenone A, (D) OCPD, and (E) dn-OPDA. Fig. 4. View largeDownload slide Chemical structures of several 12-OPDA homologues. (A) Chromomoric acid C-1, (B) 10-OPDA, (C) dicranenone A, (D) OCPD, and (E) dn-OPDA. Close homologues to OPDA have been identified in the Japanese mosses Dicranum scoporium and D. japonicum; these cyclopentenones are also known as dicranenones (Ichikawa et al., 1983). Two of the cyclopentenones contain an acetylenic side-chain bond (shown for dicraneone A, Fig. 4), but so far they have not been studied in detail. Their synthesis was described by Sakai et al. (1985). OPDA congeners with anti-cancerous effects (e.g. chromomoric acid c-1) also exist in Chromolaena odorata (Bohlmann et al., 1981; Heiss et al., 2014). The hunt for novel cyclopentenone derivatives has included plants (see reviews by Panossian, 1987; Groenewald and Van der Westhuizen, 1997), marine algae (Barbosa et al., 2016), corals (Grechkin, 1995), and humans (Straus and Glass, 2001), and should be expanded to other phylogenetic groups. Evolution of 12-OPDA The occurrence of OPDA-like compounds and OPDA in marine algae (Ritter et al., 2008; Barbosa et al., 2016), and OPDA in land plants such as the terrestrial alga Klebsormidium flaccidum (Yamamoto et al., 2015), the mosses P. patens (Stumpe et al., 2010), Marchantia polymorpha (Yamamoto et al., 2015), and the fern Selaginella martensii (Ogorodnikova et al., 2015) suggests that its origin occurred in the time before the radiation of the green lineage more than 450 million years ago. A recent breakthrough by Monte et al. (2018) revealed that dn-OPDA is the evolutionary precursor of JA-Ile, the active form of JA. By considering the receptor of JA-Ile (COI 1 in Marchantia and the orthologue in the vascular plant Arabidopsis), the authors could demonstrate that Marchantia COI1 did not respond to JA-Ile, but it did respond to dn-OPDA. In addition, they reasoned that the non-polarity of dn-OPDA exerted evolutionary pressure for formation of the polar JA-Ile hormone, which is easily distributable through the vasculature. The presence of OPDA and the absence of JA-Ile in Marchantia and the co-appearance of both in early vascular plants such as ferns suggest that 12-OPDA is older than jasmonic acid. Taking into consideration the co-evolution of herbivores and vascular plants (Farmer, 2014), it is reasonable to speculate that the functions of 12-OPDA expanded and diversified into JA-Ile. The evolution of the enzymes involved has also been discussed (Lee et al., 2008; Andreou et al., 2009; Han et al., 2017). Outlook The cyPG-like features of OPDA are evident, as described in this review. Detailed inspection of the protein structures of enzymes involved in human and plant pathways may help to derive the common ancestor for oxylipin synthesis. OPDA regulates defense responses, redox homeostasis, and embryo development, but we know little about the signal transduction pathways involved. Information about protein interactors of OPDA is also scarce. Knowledge of human cyPGylated proteins may provide clues to the OPDA interactome. The OPDA synthesis strategies that have been developed recently (as summarized in this review) will foster research aimed at identifying the effector proteins of OPDA, elucidating the mechanisms of sensing and transmission, and providing a deeper analysis of physiological responses. There is a need to examine the compartmentation and transport of 12-OPDA and its conjugates in planta, over long distances as well as short. A candidate protein for long-distance transport is the acyl-CoA binding protein 6 (ACBP 6) expressed in the phloem (Ye et al., 2016). Imaging mass spectroscopy has recently been applied to study 12-OPDA distribution in specific cell layers in seeds (Enomoto et al., 2017). Novel methodologies and highly sensitive targeted analytics such as this can be used to detect the conditional occurrence of OPDA conjugates, and to identify effector proteins and their physiological significance. This review has summarized the significant advancements achieved over the last 40 years of research, and also indicates routes towards comprehensively elucidating the multiple functions and the potential of OPDA in medicine. Acknowledgements We wish to thank Jana Löwe for fruitful discussions concerning the synthesis of 12-OPDA homologues. This own work was supported by the Deutsche Forschungsgemeinschaft (DI346; SPP1710). We also gratefully acknowledge support by the University of Bielefeld. The authors declare that they have no conflicts of interest. References Ainai T , Matsuumi M , Kobayashi Y . 2003 . Efficient total synthesis of 12-oxo-PDA and OPC-8:0 . The Journal of Organic Chemistry 68 , 7825 – 7832 . 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TI - The function of the oxylipin 12-oxophytodienoic acid in cell signaling, stress acclimation, and development
JF - Journal of Experimental Botany
DO - 10.1093/jxb/ery316
DA - 2018-11-26
UR - https://www.deepdyve.com/lp/oxford-university-press/the-function-of-the-oxylipin-12-oxophytodienoic-acid-in-cell-signaling-ILUABK69C7
SP - 5341
VL - 69
IS - 22
DP - DeepDyve
ER -