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BRENDA in 2019: a European ELIXIR core data resource

BRENDA in 2019: a European ELIXIR core data resource Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D542–D549 Nucleic Acids Research, 2019, Vol. 47, Database issue Published online 5 November 2018 doi: 10.1093/nar/gky1048 BRENDA in 2019: a European ELIXIR core data resource Lisa Jeske, Sandra Placzek, Ida Schomburg, Antje Chang and Dietmar Schomburg Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universitat ¨ Braunschweig, Rebenring 56, 38106 Braunschweig, Germany Received September 14, 2018; Revised October 05, 2018; Editorial Decision October 10, 2018; Accepted October 30, 2018 ABSTRACT and has developed to the world’s main repository on enzyme properties, used by up to 100 000 users per month. The BRENDA enzyme database (www.brenda- Since 1998 the website is available via the world wide web enzymes.org), recently appointed ELIXIR Core Data and has been evolved to an essential encyclopedia, meeting Resource, is the main enzyme and enzyme-ligand the requirements of the users in connection with the fast information system. The core database provides a growing number of data (‘big data’) and new developments comprehensive overview on enzymes. A collection of in the ‘OMICS’ community in the area of the systems biology, biotechnology, medical and pharmaceutical 4.3 million data for ∼84 000 enzymes manually eval- research. uated and extracted from ∼140 000 primary literature The BRENDA website provides a comprehensive references is combined with information obtained overview on enzymes and combines its data content with by text and data mining, data integration and pre- a sophisticated flexible query system with analysis and diction algorithms. Supplements comprise disease- visualization tools, and data retrieval options for detailed related data, protein sequences, 3D structures, pre- assessment of enzyme data in more than 50 categories of dicted enzyme locations and genome annotations. enzyme properties. The contents in BRENDA encompasses Major developments are a revised ligand summary data on the catalyzed reaction, nomenclature, taxonomy, page and the structure search now including a simi- enzyme–ligand interaction, inhibition, occurrence, stabil- larity and isomer search. BKMS-react, an integrated ity, kinetics, mutants, application, protein sequence and database containing known enzyme-catalyzed reac- structure, disease-related data, etc. tions, is supplemented with further reactions and im- The data collection is based on the EC classification sys- tem of the IUBMB (International Union of Biochemistry proved access to pathway connections. In addition to and Molecular Biology, (2)), and the main core contains 4.3 existing enzyme word maps with graphical informa- million manually annotated experimental enzyme data of 84 tion of enzyme specific terms, plant word maps have 000 enzymes from all taxonomic groups, evaluated and ex- been developed. They show a graphical overview of tracted by scientific experts from ∼140 000 primary litera- terms, e.g. enzyme or plant pathogen information, ture references. Each entry is linked to its literature reference connected to specific plants. An organism summary and the organism of origin. For a complete overview on the page showing all relevant information, e.g. taxon- occurrence of characterized enzymes BRENDA integrates omy and synonyms linked to enzyme data, was im- information retrieved by text mining of literature abstracts. plemented. Based on a decision by the IUBMB en- This set of data contains 1.6 million entries from ∼3.6 mil- zyme task force the enzyme class EC 7 has been es- lion references including information on enzyme/diseases, organisms/tissues, cellular and subcellular localization and tablished for ‘translocases’, enzymes that catalyze a kinetic values (3,4). These data are represented in the ac- transport of ions or metabolites across cellular mem- cessory modules AMENDA, FRENDA, DRENDA and branes. KENDA. The BRENDA ‘ligands’ are a fundamental part of the INTRODUCTION repository, covering all compounds interacting with en- zymes, such as substrates and products, cofactors, in- BRENDA (BRaunschweig ENzyme DAtabase, hibitors, activating compounds, etc. stored in the associ- www.brenda-enzymes.org), founded in 1987, is the ated ‘ligand’ database. Approximately 205 000 enzyme lig- main public information system for functional enzyme and ands (small molecules as well as macromolecules) are stored enzyme–ligand related information. Originally, BRENDA started as a series of books (Handbook of Enzymes, (1)) To whom correspondence should be addressed. Tel: +49 531 391 55202; Fax: +49 531 391 55199; Email: d.schomburg@tu-bs.de C The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. 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. Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 Nucleic Acids Research, 2019, Vol. 47, Database issue D543 with 1.6 million functional and structural data, which can coordinates life science resources and develops ways to be searched and displayed. store, analyze and exchange data, and implement best prac- The BRENDA Tissue Ontology (BTO) has been devel- tices. It provides platforms for computing and tools, data oped as a structured comprehensive encyclopedia of tissue storage and transfer, as well as training. ELIXIR also estab- terms from multicellular organisms (5). The BTO offers a lishes Europe-wide standards that can be used to describe direct access to information about enzymes, isolated or de- life science data (https://www.elixir-europe.org/platforms/ tected in organs, tissues, cell types and cell lines. Addition- data/core-data-resources). BRENDA is also member of ally, the human anatomy atlas CAVEman (6,7) is linked to de.NBI, the German Network for Bioinformatics Infras- the BTO terms providing a connection between anatomi- tructure (https://www.denbi.de). cal and functional enzyme data. Along with the BTO, the subcellular localization of enzyme activity is linked to the NEW DEVELOPMENTS AND MAJOR IMPROVE- entries of Gene Ontology (8). Furthermore, the BRENDA MENTS website provides the access to supplemental enzyme-related The ligand summary page data, e.g. the TaxTree Explorer, showing all organisms of the NCBI taxonomy database (9), the EC Explorer repre- In BRENDA all compounds playing a role in enzyme- senting the hierarchical EC classification of the IUBMB, catalyzed reactions (e.g. substrates, products, activators, in- both directly linked to the BRENDA enzyme summary hibitors and cofactors) are referred to as ‘ligands’. The in- pages. The 3D-structural classification of enzyme proteins formation about each ligand is combined and presented on is covered by SCOPe and CATH (10,11). the ligand summary page. The EnzymeDetector was integrated into BRENDA in In addition to structural information like a graphical 2011 (12) and was substantially improved in 2014 offer- structure diagram, a molecular formula and the InChIKey, ing an automatic comparison, evaluation and prediction sets of synonyms and a representative name of the ligand of enzyme function annotations for bacterial and archaeal are given at the top of the page. A link to all known path- genomes. ways associated with the ligand is located below this basic In addition to the supplement data, BRENDA provides ligand information. data and information of external databases, e.g. protein se- The respective data fields of the ligand roles mentioned quences (UniProt, (13)), 3D structures (PDB, (14)), KEGG above are linked to an EC number, a reference and an en- and MetaCyc pathways (15,16), genome annotations in the zyme 3D structure (see Figure 1A). Enzyme kinetic param- Genome Explorer (17) and links to PubMed (18) for the lit- eters, such as the k value, K value, K value and IC cat M i 50 erature references. value are also listed in combination with an EC number and Since the last publication in 2017 new developments a reference. and major improvements are implemented in BRENDA. The last section contains all literature references of the The ligand summary page (19) is upgraded and endowed ligand in BRENDA as well as links to ChEBI (23) and Pub- with new functions, new links and user-optimized features. Chem (24). The chemical substructure search (20) is essentially revised Due to the substantial increase of data the ligand sum- and extended with new search options, more information mary pages have recently been optimized and now present a fields and new links, as well as an optimized display of view similar to the enzyme summary pages. Users can adapt the search results. The BKMS-react database is substan- the appearance of the website according to their own re- tially improved, supplemented with further reactions and quirements and display only data fields of interest. Similar a new access to pathway connections. In addition to the ex- records in the tables are summarized and can be made vis- isting word maps, which provide graphical information of ible by click or mouseover. Sorting options have been im- terms associated with specific enzymes, new plant word maps plemented for the columns. The individually chosen format have been implemented. They show a graphical overview of the ligand summary page can be printed using the new of terms, e.g. enzyme or plant pathogen information con- function ‘print visible entries’ in the upper right corner. nected to specific plants. In this context a new organism summary page showing all relevant information, e.g. taxon- The revised and extended BRENDA structure search omy and synonyms linked to the enzyme data, was imple- mented. The 3D protein structures in BRENDA are now The BRENDA structure search is an instrument for draw- linked to DoGSiteScorer and Protoss (21). These two ap- ing a chemical structure with the JSME molecule editor proaches predict the druggablity and the protonation states (25) and searching it in ∼134 000 different molecular struc- of proteins, respectively. tures covering ∼186 000 different compound names of the BRENDA ligand database among substrates, products, in- hibitors, activating compounds and cofactors. BRENDA - A EUROPEAN ELIXIR CORE DATA RE- The search form provides three different search types. In SOURCE addition to the former substructure search which identified In June 2018, BRENDA was selected by ELIXIR as a Core all BRENDA molecules containing the drawn structure, a Data Resource, the prestigious list of databases which are similarity and an isomer search have been implemented. critically important for life science research (22). ELIXIR The substructure and isomer searches first carry out a fin- is an intergovernmental organization that brings together gerprint scan followed by a graph-matching algorithm. A high-quality life science resources from across Europe to en- fingerprint of a molecule is a unique identifier of the respec- sure the long-term preservation of life science data. ELIXIR tive chemical structure. This identifier is based on all paths Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D544 Nucleic Acids Research, 2019, Vol. 47, Database issue Figure 1. (A)The ligand summary page of acetylcholinesterase inhibitor tacrine containing the inhibitor table linked with enzyme 3D structures. The user can click at the (+)-icon to show the specific data of the EC number 3.1.1.7 or click at the ( −)-icon to hide it. (B) 3D-structure search result page of acetylcholinesterase accessible via the entry page using the ‘Classic View’. (C) 3D enzyme structure of acetylcholinesterase in combination with tacrine. of atoms and bonds within the molecule with a maximal tions informs about the current status of the process. Before length of eight atoms. The graph matching algorithm then calculations the BRENDA ligands are sorted by their num- transforms the molecular structures into undirected graphs. ber of atoms. The result table first displays the most similar Thus, a molecule is represented as a network where atoms structures. Additionally, the results can be filtered accord- form the nodes and bonds are the edges. Atoms and bonds ing to the occurrence of the respective molecules in living of the drawn structure are compared with the BRENDA organisms or their involvement in enzyme classes (EC num- ligand structures and then matched. The pre-selection of bers). promising molecules with the fingerprint scan is executed as the first step to reduce the number of these time-consuming The integrated biochemical reaction database BKMS-react graph matchings. The substructure and isomer searches are different in The creation of complete and reliable metabolic models re- the matching algorithm types. In the substructure search, a quires associated data of the scientific literature for reac- subgraph-matching algorithm is used, whereas a complete tions. This information can be extracted from curated bi- matching of the graph is calculated in the isomer search ex- ological databases, such as BRENDA, KEGG, MetaCyc cluding the spatial arrangement of the atoms. and SABIO-RK (27). Since the amount and annotation In the similarity search only the fingerprint scan is car- of reactions differ between these sources, the easy and si- ried out taking into account the Tanimoto coefficient ( 26) multaneous access to all databases via the BRENDA mod- - a measure for similarity - and the previously user-defined ule BKMS-react is a great advantage. BKMS-react com- minimal similarity as lower boundary. In Figure 2, a similar- prises 69 981 unique reactions and is based on a match- ity search for known proton-pump inhibitors with the par- ing algorithm integrating all reactions of the mentioned ent structure and a minimal similarity of 60% is displayed. databases by a comparison of compound structures and As the result, the user gets a list of all matching ligands names. The distribution of unique reactions between the with information about synonyms, their roles in enzyme- databases of the release 2018.2 is illustrated in Figure 3. catalyzed reactions and the structure diagrams. If one of A total of 806 reactions occur in BRENDA and KEGG these ligands is of particular interest, it is possible to start and 23 reactions in MetaCyc and SABIO-RK (not shown a BRENDA search or visit the respective ligand summary in Figure 3). BRENDA reactions provide the largest part page for more information, such as pathways, associated EC with a total of 56 778 unique reactions of which 47 456 can numbers, reaction equations, references, enzyme kinetic pa- only be found in BRENDA. rameters, the molfile and the InChIKey. Recently, the original website BKM-react was supple- In addition to the new search types the search form and mented with reactions of the biochemical reaction kinetics result pages have been more clearly arranged. Since the database SABIO-RK and renamed BKMS-react. Addition- matching algorithms are very time-consuming, the user can ally, the new tab ‘Pathways’ provides a quick overview on select a maximal search time. A progress bar with notifica- all pathways of BRENDA, KEGG and MetaCyc associated Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 Nucleic Acids Research, 2019, Vol. 47, Database issue D545 Figure 2. A similarity search for known proton-pump inhibitors with the parent structure. ing at a BRENDA pathway in the reaction entry (see Figure 4). Organism word maps and organism summary pages In 2015 BRENDA introduced the enzyme word maps pro- viding a quick overview on enzyme research areas as found in the literature. Now, BRENDA provides a wider spec- trum with the new organism word maps. The first beta ver- sion of the organism word maps as well as the organism summary pages are available for the taxonomic groups of Archaea, Bacteria, Fungi as well as Viridiplantae and will be extended to all taxonomic groups. This new option of- fers a quick and easy access of relevant facts published in PubMed. The terms are classified with respect to the en- zyme, organism, human disease, plant disease, plant trait, plant pathogen, useful organism and habitat. In the same manner, specified for the enzyme word maps the information is categorized in different colors and font sizes depending on their relevance, category and specificity. Within a word map Figure 3. Distribution of unique reactions between BRENDA, KEGG, the entries are directly linked to available enzyme-related in- MetaCyc and SABIO-RK, not shown are the number of common reac- formation and to the new organism summary pages (Figure tions of BRENDA/KEGG and MetaCyc/SABIO-RK. 5). The organism summary page provides the access to a wide range of information about each organism, including the scientific name, synonyms, enzymes, pathways, source tis- with at least one reaction of BKMS-react. After choosing a sue and subcellular localization connected to the BRENDA specific pathway the respective reactions appear in the result data. The classification within the taxonomic tree is dis- table. Furthermore, a reaction-specific pathway view with a played and linked directly to the NCBI Taxonomy, PubMed blue highlighted EC number node can be retrieved by click- and to the NCBI Genome are given. Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D546 Nucleic Acids Research, 2019, Vol. 47, Database issue Figure 4. A reaction specific pathway view of the vitamin E metabolism in BKMS-react. Figure 5. Organism summary page of Glycine max. Enzyme 3D structures linked with Protoss and acetylcholinesterase as illustrated in Figure 1B. Acetyl- DoGSiteScorer cholinesterase catalyzes the degradation of the neurotrans- mitter acetylcholine. A 3D image of the enzyme structure Links to DoGSiteScorer (28) (‘enzyme pockets’) and Pro- with the active site in yellow and the inhibitor tacrine in toss (29) (‘protonated enzyme’), developed by the Rarey gray/blue is shown by clicking at ‘3D-view’ (see Figure 1C). group at the Center of Bioinformatics, University of Ham- Tacrine is a known acetylcholinesterase inhibitor used for burg were integrated into the 3D-structure search re- symptomatic treatment of Alzheimer’s disease (30). sult pages in release 2017.1. An example is given for Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 Nucleic Acids Research, 2019, Vol. 47, Database issue D547 DoGSiteScorer is a software for druggability predictions from natural sources have gained much scientific interest. based on the detection of potential binding pockets. For Thus, extensive data were added to the respective enzyme predicted pockets, the size, shape, chemical features and a classes (e.g. cellulases, glycohydrolases). Suitable enzymes druggability score are provided. were found in fungi, bacteria and some archaea. Among Protoss completes the hydrogen bonding network of the bacterial and archaeal enzymes, some candidates show a protein–ligand complexes by adding missing hydrogen good stability in the harsh conditions, which may occur dur- atoms. Protonation states, tautomers, hydrogen coordi- ing biofuel processing. The fungal enzymes however show nates, metal interactions and repulsive forces between atoms a broader substrate spectrum, including branched polysac- are considered in this process. charides which are part of the hemicelluloses. Unfortu- nately, these enzymes are rarely active above 60 C. A liter- DRENDA - disease information on enzymes ature search for fungal habitats with elevated temperatures retrieved only a few species from the genus Thermomyces. Enzymes play an important and often essential role in the development or treatment of many diseases, either as causing agents (malfunction), used for diagnosis, or dur- New enzyme class 7 - an important innovation of the nomen- ing treatment as a drug target (e.g. in infection and many clature system others). By a combination of text mining in titles and ab- stracts of papers cited in PubMed and supervised classifi- In 1961, the enzyme commission of the International Union cation by support vector machines, 844 260 journal articles of Biochemistry established the fundamental scheme of en- were identified that cover enzyme and disease aspects. A to- zyme classification based on the catalyzed reactions. Six tal of 495 579 of them are describing causal interactions, 423 main classes were established at that time. Sub- and sub- 256 diagnostic applications and 330 545 roles of enzymes in subclasses have been added since, but no changes had been therapy. By choosing a confidence level the user can either necessary regarding the main classes. With the new EC class select a high precision or a high recall of the results. A to- 7 this will now be a major change in the EC system of en- tal of 890 842 enzyme disease relations were identified. A zyme classification. combined search based on disease, enzyme and title con- For cell growth and metabolism, all organisms need en- tents allows a highly specific search for relevant papers ( 31). zymes for transporting compounds across cellular mem- Additionally, the MESH ontology (32)informofatree branes. Several of these transports are driven by the hydroly- viewer has been added to the user interface. This provides a sis of adenosine triphosphate and the enzymes were accord- fast overview on the enzymes involved in a certain disease. ingly classified as hydrolases in EC 3.6.3.-. However, their An ontology is a presentation of terms and their logical re- primary function is the transport across a membrane and lationships. The ontology explorer in BRENDA comprises not the hydrolytic reaction. A new EC main class 7 named a variety of 35 biologically and biochemically relevant on- ‘Translocases’ was recently established by the IUBMB. The tologies. The MeSH Ontology, a hierarchical terminology reactions catalyzed are designated as transfers from ‘side 1’ for indexing biomedical literature, is such an ontology used to ‘side 2’. Older designations like ‘in’ and ‘out’ (or ‘cis’ and for the classification of PubMed papers. The terms of the ‘trans’) were discarded since they can be ambiguous. The branch ‘Diseases’ are used in DRENDA (Disease Related new class and its currently populated subclasses are defined ENzyme information DAtabase). as follows: New contents in BRENDA EC 7 Translocases EC 7.1 Catalyzing the translocation of hydrons The current database release (August 2018) covers 7590 EC 7.1.1 Hydron translocation or charge separation enzyme classes (EC numbers), including 292 deleted, 610 linked to oxidoreductase reactions transferred and 498 preliminary classes. Since September EC 7.1.2 Hydron translocation linked to the hydrolysis 2016, the number of EC classes increased by 598, of which of a nucleoside triphosphate 110 originated from transfers of older classes. Transfers are EC 7.1.3 Hydron translocation linked to the hydrolysis discussed and decided by the IUBMB enzyme task force of diphosphate with active participation of the BRENDA team. They be- come necessary when newly published enzyme data prove EC 7.2 Catalyzing the translocation of inorganic cations that the enzyme acts in a different way than originally de- EC 7.2.1 Linked to oxidoreductase reactions scribed. EC 7.2.2 Linked to the hydrolysis of a nucleoside triphos- Since our last publication (33) the data for 3236 EC phate classes were updated. New information for the ∼60 data EC 7.2.3 Hydron translocation linked to the hydrolysis fields was added by manual annotation of ∼9500 additional of diphosphate literature references. This information characterizes each EC 7.2.4 Linked to decarboxylation enzyme with respect to its catalyzed reactions and speci- EC 7.3 Catalyzing the translocation of inorganic anions ficity, kinetic properties, experimental conditions, stability and their chelates and sensitivity to inhibitory agents. The current data con- EC 7.3.2 Linked to the hydrolysis of a nucleoside triphos- tent for a selection of data fields is shown in Table 1. Spe- phate cial emphasis in recent data annotation was laid upon en- EC 7.4 Catalyzing the translocation of amino acids and zymes degrading polysaccharides and lignin in plant ma- peptides terials. Biotechnological processes of biofuel production Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D548 Nucleic Acids Research, 2019, Vol. 47, Database issue Table 1. Number of entries in selected data fields Enzyme information Entries 2016 Entries 2018 Substrates and products 407 446 435 289 Inhibitors 196 548 207 441 Cofactors 14 382 15 964 Metals and ions 36 711 38 548 Activating compounds 26 761 27 653 K -Values 135 603 145 215 K Values 38 378 39 927 i- k -Values 62 445 68 963 cat Specific activity 45 773 48 001 IC - Values 49 842 54 230 Localization and source/tissue 96 889 102 758 Enzyme names and synonyms 102 394 111 488 Citations (manually annotated) 146 221 155 422 Isolation and preparation/crystallization 88 849 96 765 Enzyme structure 158 397 196 071 Mutant enzymes 76 451 83 355 Enzyme stability 47 281 49 271 Enzyme application 15 080 16 441 The numbers refer to the combination of enzyme protein, source organism and literature reference. The term enzyme protein refers either to a protein se- quence or to a protein isolated from a given organism without its sequence having been determined. EC 7.4.2 Linked to the hydrolysis of a nucleoside triphos- 3. Chang,A., Scheer,M., Grote,A., Schomburg,I. and Schomburg,D. (2009) BRENDA, AMENDA and FRENDA the enzyme phate information system: new content and tools in 2009. Nucleic Acids EC 7.5 Catalyzing the translocation of carbohydrates Res., 37, 588–592. and their derivatives 4. Schomburg,I., Chang,A., Placzek,S., Sohngen,C ¨ ., Rother,M., Lang,M., Munaretto,C., Ulas,S., Stelzer,M., Grote,A. et al. (2013) EC 7.5.2 Linked to the hydrolysis of a nucleoside triphos- BRENDA in 2013: integrated reactions, kinetic data, enzyme phate function data, improved disease classification: new options and contents in BRENDA. Nucleic Acids Res., 41, 764–772. EC 7.6 Catalyzing the translocation of other compounds 5. Gremse,M., Chang,A., Schomburg,I., Grote,A., Scheer,M., EC 7.6.2 Linked to the hydrolysis of a nucleoside triphos- Ebeling,C. and Schomburg,D. 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Durinx,C., McEntyre,J., Appel,R., Apweiler,R., Barlow,M., classification scheme for disease-related enzyme information. BMC Blomberg,N., Cook,C., Gasteiger,E., Kim,J.-H., Lopez,R. et al. Bioinformatics, 12, 329. (2017) Identifying ELIXIR core data resources [version 2; referees:2 32. Sewell,W. (1964) Medical subject headings in medlars. Bull. Med. approved]. F1000 Res., 5, 2422. Libr. Assoc., 52, 164–170. 23. Hastings,J., Owen,G., Dekker,A., Ennis,M., Kale,N., 33. Placzek,S., Schomburg,I., Chang,A., Jeske,L., Ulbrich,M., Tillack,J. Muthukrishnan,V., Turner,S., Swainston,N., Mendes,P. and and Schomburg,D. (2017) BRENDA in 2017: new perspectives and Steinbeck,C. (2016) ChEBI in 2016: improved services and an new tools in BRENDA. Nucleic Acids Res., 45, D380–D388. expanding collection of metabolites. Nucleic Acids Res., 44, D1214–D1219. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nucleic Acids Research Oxford University Press

BRENDA in 2019: a European ELIXIR core data resource

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© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
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Abstract

Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D542–D549 Nucleic Acids Research, 2019, Vol. 47, Database issue Published online 5 November 2018 doi: 10.1093/nar/gky1048 BRENDA in 2019: a European ELIXIR core data resource Lisa Jeske, Sandra Placzek, Ida Schomburg, Antje Chang and Dietmar Schomburg Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universitat ¨ Braunschweig, Rebenring 56, 38106 Braunschweig, Germany Received September 14, 2018; Revised October 05, 2018; Editorial Decision October 10, 2018; Accepted October 30, 2018 ABSTRACT and has developed to the world’s main repository on enzyme properties, used by up to 100 000 users per month. The BRENDA enzyme database (www.brenda- Since 1998 the website is available via the world wide web enzymes.org), recently appointed ELIXIR Core Data and has been evolved to an essential encyclopedia, meeting Resource, is the main enzyme and enzyme-ligand the requirements of the users in connection with the fast information system. The core database provides a growing number of data (‘big data’) and new developments comprehensive overview on enzymes. A collection of in the ‘OMICS’ community in the area of the systems biology, biotechnology, medical and pharmaceutical 4.3 million data for ∼84 000 enzymes manually eval- research. uated and extracted from ∼140 000 primary literature The BRENDA website provides a comprehensive references is combined with information obtained overview on enzymes and combines its data content with by text and data mining, data integration and pre- a sophisticated flexible query system with analysis and diction algorithms. Supplements comprise disease- visualization tools, and data retrieval options for detailed related data, protein sequences, 3D structures, pre- assessment of enzyme data in more than 50 categories of dicted enzyme locations and genome annotations. enzyme properties. The contents in BRENDA encompasses Major developments are a revised ligand summary data on the catalyzed reaction, nomenclature, taxonomy, page and the structure search now including a simi- enzyme–ligand interaction, inhibition, occurrence, stabil- larity and isomer search. BKMS-react, an integrated ity, kinetics, mutants, application, protein sequence and database containing known enzyme-catalyzed reac- structure, disease-related data, etc. tions, is supplemented with further reactions and im- The data collection is based on the EC classification sys- tem of the IUBMB (International Union of Biochemistry proved access to pathway connections. In addition to and Molecular Biology, (2)), and the main core contains 4.3 existing enzyme word maps with graphical informa- million manually annotated experimental enzyme data of 84 tion of enzyme specific terms, plant word maps have 000 enzymes from all taxonomic groups, evaluated and ex- been developed. They show a graphical overview of tracted by scientific experts from ∼140 000 primary litera- terms, e.g. enzyme or plant pathogen information, ture references. Each entry is linked to its literature reference connected to specific plants. An organism summary and the organism of origin. For a complete overview on the page showing all relevant information, e.g. taxon- occurrence of characterized enzymes BRENDA integrates omy and synonyms linked to enzyme data, was im- information retrieved by text mining of literature abstracts. plemented. Based on a decision by the IUBMB en- This set of data contains 1.6 million entries from ∼3.6 mil- zyme task force the enzyme class EC 7 has been es- lion references including information on enzyme/diseases, organisms/tissues, cellular and subcellular localization and tablished for ‘translocases’, enzymes that catalyze a kinetic values (3,4). These data are represented in the ac- transport of ions or metabolites across cellular mem- cessory modules AMENDA, FRENDA, DRENDA and branes. KENDA. The BRENDA ‘ligands’ are a fundamental part of the INTRODUCTION repository, covering all compounds interacting with en- zymes, such as substrates and products, cofactors, in- BRENDA (BRaunschweig ENzyme DAtabase, hibitors, activating compounds, etc. stored in the associ- www.brenda-enzymes.org), founded in 1987, is the ated ‘ligand’ database. Approximately 205 000 enzyme lig- main public information system for functional enzyme and ands (small molecules as well as macromolecules) are stored enzyme–ligand related information. Originally, BRENDA started as a series of books (Handbook of Enzymes, (1)) To whom correspondence should be addressed. Tel: +49 531 391 55202; Fax: +49 531 391 55199; Email: d.schomburg@tu-bs.de C The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. 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. Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 Nucleic Acids Research, 2019, Vol. 47, Database issue D543 with 1.6 million functional and structural data, which can coordinates life science resources and develops ways to be searched and displayed. store, analyze and exchange data, and implement best prac- The BRENDA Tissue Ontology (BTO) has been devel- tices. It provides platforms for computing and tools, data oped as a structured comprehensive encyclopedia of tissue storage and transfer, as well as training. ELIXIR also estab- terms from multicellular organisms (5). The BTO offers a lishes Europe-wide standards that can be used to describe direct access to information about enzymes, isolated or de- life science data (https://www.elixir-europe.org/platforms/ tected in organs, tissues, cell types and cell lines. Addition- data/core-data-resources). BRENDA is also member of ally, the human anatomy atlas CAVEman (6,7) is linked to de.NBI, the German Network for Bioinformatics Infras- the BTO terms providing a connection between anatomi- tructure (https://www.denbi.de). cal and functional enzyme data. Along with the BTO, the subcellular localization of enzyme activity is linked to the NEW DEVELOPMENTS AND MAJOR IMPROVE- entries of Gene Ontology (8). Furthermore, the BRENDA MENTS website provides the access to supplemental enzyme-related The ligand summary page data, e.g. the TaxTree Explorer, showing all organisms of the NCBI taxonomy database (9), the EC Explorer repre- In BRENDA all compounds playing a role in enzyme- senting the hierarchical EC classification of the IUBMB, catalyzed reactions (e.g. substrates, products, activators, in- both directly linked to the BRENDA enzyme summary hibitors and cofactors) are referred to as ‘ligands’. The in- pages. The 3D-structural classification of enzyme proteins formation about each ligand is combined and presented on is covered by SCOPe and CATH (10,11). the ligand summary page. The EnzymeDetector was integrated into BRENDA in In addition to structural information like a graphical 2011 (12) and was substantially improved in 2014 offer- structure diagram, a molecular formula and the InChIKey, ing an automatic comparison, evaluation and prediction sets of synonyms and a representative name of the ligand of enzyme function annotations for bacterial and archaeal are given at the top of the page. A link to all known path- genomes. ways associated with the ligand is located below this basic In addition to the supplement data, BRENDA provides ligand information. data and information of external databases, e.g. protein se- The respective data fields of the ligand roles mentioned quences (UniProt, (13)), 3D structures (PDB, (14)), KEGG above are linked to an EC number, a reference and an en- and MetaCyc pathways (15,16), genome annotations in the zyme 3D structure (see Figure 1A). Enzyme kinetic param- Genome Explorer (17) and links to PubMed (18) for the lit- eters, such as the k value, K value, K value and IC cat M i 50 erature references. value are also listed in combination with an EC number and Since the last publication in 2017 new developments a reference. and major improvements are implemented in BRENDA. The last section contains all literature references of the The ligand summary page (19) is upgraded and endowed ligand in BRENDA as well as links to ChEBI (23) and Pub- with new functions, new links and user-optimized features. Chem (24). The chemical substructure search (20) is essentially revised Due to the substantial increase of data the ligand sum- and extended with new search options, more information mary pages have recently been optimized and now present a fields and new links, as well as an optimized display of view similar to the enzyme summary pages. Users can adapt the search results. The BKMS-react database is substan- the appearance of the website according to their own re- tially improved, supplemented with further reactions and quirements and display only data fields of interest. Similar a new access to pathway connections. In addition to the ex- records in the tables are summarized and can be made vis- isting word maps, which provide graphical information of ible by click or mouseover. Sorting options have been im- terms associated with specific enzymes, new plant word maps plemented for the columns. The individually chosen format have been implemented. They show a graphical overview of the ligand summary page can be printed using the new of terms, e.g. enzyme or plant pathogen information con- function ‘print visible entries’ in the upper right corner. nected to specific plants. In this context a new organism summary page showing all relevant information, e.g. taxon- The revised and extended BRENDA structure search omy and synonyms linked to the enzyme data, was imple- mented. The 3D protein structures in BRENDA are now The BRENDA structure search is an instrument for draw- linked to DoGSiteScorer and Protoss (21). These two ap- ing a chemical structure with the JSME molecule editor proaches predict the druggablity and the protonation states (25) and searching it in ∼134 000 different molecular struc- of proteins, respectively. tures covering ∼186 000 different compound names of the BRENDA ligand database among substrates, products, in- hibitors, activating compounds and cofactors. BRENDA - A EUROPEAN ELIXIR CORE DATA RE- The search form provides three different search types. In SOURCE addition to the former substructure search which identified In June 2018, BRENDA was selected by ELIXIR as a Core all BRENDA molecules containing the drawn structure, a Data Resource, the prestigious list of databases which are similarity and an isomer search have been implemented. critically important for life science research (22). ELIXIR The substructure and isomer searches first carry out a fin- is an intergovernmental organization that brings together gerprint scan followed by a graph-matching algorithm. A high-quality life science resources from across Europe to en- fingerprint of a molecule is a unique identifier of the respec- sure the long-term preservation of life science data. ELIXIR tive chemical structure. This identifier is based on all paths Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D544 Nucleic Acids Research, 2019, Vol. 47, Database issue Figure 1. (A)The ligand summary page of acetylcholinesterase inhibitor tacrine containing the inhibitor table linked with enzyme 3D structures. The user can click at the (+)-icon to show the specific data of the EC number 3.1.1.7 or click at the ( −)-icon to hide it. (B) 3D-structure search result page of acetylcholinesterase accessible via the entry page using the ‘Classic View’. (C) 3D enzyme structure of acetylcholinesterase in combination with tacrine. of atoms and bonds within the molecule with a maximal tions informs about the current status of the process. Before length of eight atoms. The graph matching algorithm then calculations the BRENDA ligands are sorted by their num- transforms the molecular structures into undirected graphs. ber of atoms. The result table first displays the most similar Thus, a molecule is represented as a network where atoms structures. Additionally, the results can be filtered accord- form the nodes and bonds are the edges. Atoms and bonds ing to the occurrence of the respective molecules in living of the drawn structure are compared with the BRENDA organisms or their involvement in enzyme classes (EC num- ligand structures and then matched. The pre-selection of bers). promising molecules with the fingerprint scan is executed as the first step to reduce the number of these time-consuming The integrated biochemical reaction database BKMS-react graph matchings. The substructure and isomer searches are different in The creation of complete and reliable metabolic models re- the matching algorithm types. In the substructure search, a quires associated data of the scientific literature for reac- subgraph-matching algorithm is used, whereas a complete tions. This information can be extracted from curated bi- matching of the graph is calculated in the isomer search ex- ological databases, such as BRENDA, KEGG, MetaCyc cluding the spatial arrangement of the atoms. and SABIO-RK (27). Since the amount and annotation In the similarity search only the fingerprint scan is car- of reactions differ between these sources, the easy and si- ried out taking into account the Tanimoto coefficient ( 26) multaneous access to all databases via the BRENDA mod- - a measure for similarity - and the previously user-defined ule BKMS-react is a great advantage. BKMS-react com- minimal similarity as lower boundary. In Figure 2, a similar- prises 69 981 unique reactions and is based on a match- ity search for known proton-pump inhibitors with the par- ing algorithm integrating all reactions of the mentioned ent structure and a minimal similarity of 60% is displayed. databases by a comparison of compound structures and As the result, the user gets a list of all matching ligands names. The distribution of unique reactions between the with information about synonyms, their roles in enzyme- databases of the release 2018.2 is illustrated in Figure 3. catalyzed reactions and the structure diagrams. If one of A total of 806 reactions occur in BRENDA and KEGG these ligands is of particular interest, it is possible to start and 23 reactions in MetaCyc and SABIO-RK (not shown a BRENDA search or visit the respective ligand summary in Figure 3). BRENDA reactions provide the largest part page for more information, such as pathways, associated EC with a total of 56 778 unique reactions of which 47 456 can numbers, reaction equations, references, enzyme kinetic pa- only be found in BRENDA. rameters, the molfile and the InChIKey. Recently, the original website BKM-react was supple- In addition to the new search types the search form and mented with reactions of the biochemical reaction kinetics result pages have been more clearly arranged. Since the database SABIO-RK and renamed BKMS-react. Addition- matching algorithms are very time-consuming, the user can ally, the new tab ‘Pathways’ provides a quick overview on select a maximal search time. A progress bar with notifica- all pathways of BRENDA, KEGG and MetaCyc associated Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 Nucleic Acids Research, 2019, Vol. 47, Database issue D545 Figure 2. A similarity search for known proton-pump inhibitors with the parent structure. ing at a BRENDA pathway in the reaction entry (see Figure 4). Organism word maps and organism summary pages In 2015 BRENDA introduced the enzyme word maps pro- viding a quick overview on enzyme research areas as found in the literature. Now, BRENDA provides a wider spec- trum with the new organism word maps. The first beta ver- sion of the organism word maps as well as the organism summary pages are available for the taxonomic groups of Archaea, Bacteria, Fungi as well as Viridiplantae and will be extended to all taxonomic groups. This new option of- fers a quick and easy access of relevant facts published in PubMed. The terms are classified with respect to the en- zyme, organism, human disease, plant disease, plant trait, plant pathogen, useful organism and habitat. In the same manner, specified for the enzyme word maps the information is categorized in different colors and font sizes depending on their relevance, category and specificity. Within a word map Figure 3. Distribution of unique reactions between BRENDA, KEGG, the entries are directly linked to available enzyme-related in- MetaCyc and SABIO-RK, not shown are the number of common reac- formation and to the new organism summary pages (Figure tions of BRENDA/KEGG and MetaCyc/SABIO-RK. 5). The organism summary page provides the access to a wide range of information about each organism, including the scientific name, synonyms, enzymes, pathways, source tis- with at least one reaction of BKMS-react. After choosing a sue and subcellular localization connected to the BRENDA specific pathway the respective reactions appear in the result data. The classification within the taxonomic tree is dis- table. Furthermore, a reaction-specific pathway view with a played and linked directly to the NCBI Taxonomy, PubMed blue highlighted EC number node can be retrieved by click- and to the NCBI Genome are given. Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D546 Nucleic Acids Research, 2019, Vol. 47, Database issue Figure 4. A reaction specific pathway view of the vitamin E metabolism in BKMS-react. Figure 5. Organism summary page of Glycine max. Enzyme 3D structures linked with Protoss and acetylcholinesterase as illustrated in Figure 1B. Acetyl- DoGSiteScorer cholinesterase catalyzes the degradation of the neurotrans- mitter acetylcholine. A 3D image of the enzyme structure Links to DoGSiteScorer (28) (‘enzyme pockets’) and Pro- with the active site in yellow and the inhibitor tacrine in toss (29) (‘protonated enzyme’), developed by the Rarey gray/blue is shown by clicking at ‘3D-view’ (see Figure 1C). group at the Center of Bioinformatics, University of Ham- Tacrine is a known acetylcholinesterase inhibitor used for burg were integrated into the 3D-structure search re- symptomatic treatment of Alzheimer’s disease (30). sult pages in release 2017.1. An example is given for Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 Nucleic Acids Research, 2019, Vol. 47, Database issue D547 DoGSiteScorer is a software for druggability predictions from natural sources have gained much scientific interest. based on the detection of potential binding pockets. For Thus, extensive data were added to the respective enzyme predicted pockets, the size, shape, chemical features and a classes (e.g. cellulases, glycohydrolases). Suitable enzymes druggability score are provided. were found in fungi, bacteria and some archaea. Among Protoss completes the hydrogen bonding network of the bacterial and archaeal enzymes, some candidates show a protein–ligand complexes by adding missing hydrogen good stability in the harsh conditions, which may occur dur- atoms. Protonation states, tautomers, hydrogen coordi- ing biofuel processing. The fungal enzymes however show nates, metal interactions and repulsive forces between atoms a broader substrate spectrum, including branched polysac- are considered in this process. charides which are part of the hemicelluloses. Unfortu- nately, these enzymes are rarely active above 60 C. A liter- DRENDA - disease information on enzymes ature search for fungal habitats with elevated temperatures retrieved only a few species from the genus Thermomyces. Enzymes play an important and often essential role in the development or treatment of many diseases, either as causing agents (malfunction), used for diagnosis, or dur- New enzyme class 7 - an important innovation of the nomen- ing treatment as a drug target (e.g. in infection and many clature system others). By a combination of text mining in titles and ab- stracts of papers cited in PubMed and supervised classifi- In 1961, the enzyme commission of the International Union cation by support vector machines, 844 260 journal articles of Biochemistry established the fundamental scheme of en- were identified that cover enzyme and disease aspects. A to- zyme classification based on the catalyzed reactions. Six tal of 495 579 of them are describing causal interactions, 423 main classes were established at that time. Sub- and sub- 256 diagnostic applications and 330 545 roles of enzymes in subclasses have been added since, but no changes had been therapy. By choosing a confidence level the user can either necessary regarding the main classes. With the new EC class select a high precision or a high recall of the results. A to- 7 this will now be a major change in the EC system of en- tal of 890 842 enzyme disease relations were identified. A zyme classification. combined search based on disease, enzyme and title con- For cell growth and metabolism, all organisms need en- tents allows a highly specific search for relevant papers ( 31). zymes for transporting compounds across cellular mem- Additionally, the MESH ontology (32)informofatree branes. Several of these transports are driven by the hydroly- viewer has been added to the user interface. This provides a sis of adenosine triphosphate and the enzymes were accord- fast overview on the enzymes involved in a certain disease. ingly classified as hydrolases in EC 3.6.3.-. However, their An ontology is a presentation of terms and their logical re- primary function is the transport across a membrane and lationships. The ontology explorer in BRENDA comprises not the hydrolytic reaction. A new EC main class 7 named a variety of 35 biologically and biochemically relevant on- ‘Translocases’ was recently established by the IUBMB. The tologies. The MeSH Ontology, a hierarchical terminology reactions catalyzed are designated as transfers from ‘side 1’ for indexing biomedical literature, is such an ontology used to ‘side 2’. Older designations like ‘in’ and ‘out’ (or ‘cis’ and for the classification of PubMed papers. The terms of the ‘trans’) were discarded since they can be ambiguous. The branch ‘Diseases’ are used in DRENDA (Disease Related new class and its currently populated subclasses are defined ENzyme information DAtabase). as follows: New contents in BRENDA EC 7 Translocases EC 7.1 Catalyzing the translocation of hydrons The current database release (August 2018) covers 7590 EC 7.1.1 Hydron translocation or charge separation enzyme classes (EC numbers), including 292 deleted, 610 linked to oxidoreductase reactions transferred and 498 preliminary classes. Since September EC 7.1.2 Hydron translocation linked to the hydrolysis 2016, the number of EC classes increased by 598, of which of a nucleoside triphosphate 110 originated from transfers of older classes. Transfers are EC 7.1.3 Hydron translocation linked to the hydrolysis discussed and decided by the IUBMB enzyme task force of diphosphate with active participation of the BRENDA team. They be- come necessary when newly published enzyme data prove EC 7.2 Catalyzing the translocation of inorganic cations that the enzyme acts in a different way than originally de- EC 7.2.1 Linked to oxidoreductase reactions scribed. EC 7.2.2 Linked to the hydrolysis of a nucleoside triphos- Since our last publication (33) the data for 3236 EC phate classes were updated. New information for the ∼60 data EC 7.2.3 Hydron translocation linked to the hydrolysis fields was added by manual annotation of ∼9500 additional of diphosphate literature references. This information characterizes each EC 7.2.4 Linked to decarboxylation enzyme with respect to its catalyzed reactions and speci- EC 7.3 Catalyzing the translocation of inorganic anions ficity, kinetic properties, experimental conditions, stability and their chelates and sensitivity to inhibitory agents. The current data con- EC 7.3.2 Linked to the hydrolysis of a nucleoside triphos- tent for a selection of data fields is shown in Table 1. Spe- phate cial emphasis in recent data annotation was laid upon en- EC 7.4 Catalyzing the translocation of amino acids and zymes degrading polysaccharides and lignin in plant ma- peptides terials. Biotechnological processes of biofuel production Downloaded from https://academic.oup.com/nar/article-abstract/47/D1/D542/5160988 by Ed 'DeepDyve' Gillespie user on 16 January 2019 D548 Nucleic Acids Research, 2019, Vol. 47, Database issue Table 1. Number of entries in selected data fields Enzyme information Entries 2016 Entries 2018 Substrates and products 407 446 435 289 Inhibitors 196 548 207 441 Cofactors 14 382 15 964 Metals and ions 36 711 38 548 Activating compounds 26 761 27 653 K -Values 135 603 145 215 K Values 38 378 39 927 i- k -Values 62 445 68 963 cat Specific activity 45 773 48 001 IC - Values 49 842 54 230 Localization and source/tissue 96 889 102 758 Enzyme names and synonyms 102 394 111 488 Citations (manually annotated) 146 221 155 422 Isolation and preparation/crystallization 88 849 96 765 Enzyme structure 158 397 196 071 Mutant enzymes 76 451 83 355 Enzyme stability 47 281 49 271 Enzyme application 15 080 16 441 The numbers refer to the combination of enzyme protein, source organism and literature reference. The term enzyme protein refers either to a protein se- quence or to a protein isolated from a given organism without its sequence having been determined. EC 7.4.2 Linked to the hydrolysis of a nucleoside triphos- 3. Chang,A., Scheer,M., Grote,A., Schomburg,I. and Schomburg,D. (2009) BRENDA, AMENDA and FRENDA the enzyme phate information system: new content and tools in 2009. Nucleic Acids EC 7.5 Catalyzing the translocation of carbohydrates Res., 37, 588–592. and their derivatives 4. Schomburg,I., Chang,A., Placzek,S., Sohngen,C ¨ ., Rother,M., Lang,M., Munaretto,C., Ulas,S., Stelzer,M., Grote,A. et al. (2013) EC 7.5.2 Linked to the hydrolysis of a nucleoside triphos- BRENDA in 2013: integrated reactions, kinetic data, enzyme phate function data, improved disease classification: new options and contents in BRENDA. Nucleic Acids Res., 41, 764–772. EC 7.6 Catalyzing the translocation of other compounds 5. Gremse,M., Chang,A., Schomburg,I., Grote,A., Scheer,M., EC 7.6.2 Linked to the hydrolysis of a nucleoside triphos- Ebeling,C. and Schomburg,D. (2011) The BRENDA Tissue Ontology phate (BTO): the first all-integrating ontology of all organisms for enzyme sources. Nucleic Acids Res., 39, 507–513. The transfer of the translocases from EC 3.6.3.- is per- 6. Turinsky,A.L., Fanea,E., Trinh,Q., Dong,X., Stromer,J.N., Shu,X., formed in batches of 10 to 30 entries, which are published Wat,S., Hallgrimsson,B., Hill,J.W., Edwards,C. et al. (2008) by the IUBMB (http://www.enzyme-database.org/newenz. Integration of genomic and medical data into a 3D atlas of human anatomy. Stud. Health Technol. Inform., 132, 526–531. php). The corresponding BRENDA data are made pub- 7. Chang,A., Schomburg,I., Placzek,S., Jeske,L., Ulbrich,M., Xiao,M., lic twice yearly in the regular BRENDA releases. The first Sensen,C.W. and Schomburg,D. (2015) BRENDA in 2015: exciting set of transferred translocases will appear in BRENDA in developments in its 25th year of existence. Nucleic Acids Res., 43, February 2019. D439–D446. 8. 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