{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T10:52:09Z","timestamp":1767178329587,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010452","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Canadian Institute for Health and Research","award":["PJT-152921"],"award-info":[{"award-number":["PJT-152921"]}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council","doi-asserted-by":"crossref","award":["RGPIN-2019-06852"],"award-info":[{"award-number":["RGPIN-2019-06852"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]},{"name":"SickKids RestraComp scholarship"},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013873","name":"Government of Ontario","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013873","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ontario Research Fund\u2013Research Excellence"},{"name":"Department of Toronto"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Constraint-based modeling is a powerful framework for studying cellular metabolism, with applications ranging from predicting growth rates and optimizing production of high value metabolites to identifying enzymes in pathogens that may be targeted for therapeutic interventions. Results from modeling experiments can be affected at least in part by the quality of the metabolic models used. Reconstructing a metabolic network manually can produce a high-quality metabolic model but is a time-consuming task. At the same time, current methods for automating the process typically transfer metabolic function based on sequence similarity, a process known to produce many false positives. We created Architect, a pipeline for automatic metabolic model reconstruction from protein sequences. First, it performs enzyme annotation through an ensemble approach, whereby a likelihood score is computed for an EC prediction based on predictions from existing tools; for this step, our method shows both increased precision and recall compared to individual tools. Next, Architect uses these annotations to construct a high-quality metabolic network which is then gap-filled based on likelihood scores from the ensemble approach. The resulting metabolic model is output in SBML format, suitable for constraints-based analyses. Through comparisons of enzyme annotations and curated metabolic models, we demonstrate improved performance of Architect over other state-of-the-art tools, notably with higher precision and recall on the eukaryote\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    and when compared to UniProt annotations in two bacterial species. Code for Architect is available at\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/ParkinsonLab\/Architect\" xlink:type=\"simple\">https:\/\/github.com\/ParkinsonLab\/Architect<\/jats:ext-link>\n                    . For ease-of-use, Architect can be readily set up and utilized using its Docker image, maintained on Docker Hub.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1010452","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T13:34:35Z","timestamp":1662644075000},"page":"e1010452","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Architect: A tool for aiding the reconstruction of high-quality metabolic models through improved enzyme annotation"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5962-5863","authenticated-orcid":true,"given":"Nirvana","family":"Nursimulu","sequence":"first","affiliation":[]},{"given":"Alan M.","family":"Moses","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9815-1189","authenticated-orcid":true,"given":"John","family":"Parkinson","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"pcbi.1010452.ref001","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41540-018-0063-2","article-title":"From metagenomic data to personalized in silico microbiotas: predicting dietary supplements for Crohn\u2019s disease","volume":"4","author":"E Bauer","year":"2018","journal-title":"NPJ Syst Biol Appl"},{"key":"pcbi.1010452.ref002","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/msb.2013.62","article-title":"Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii","volume":"9","author":"C Song","year":"2013","journal-title":"Mol Syst Biol"},{"key":"pcbi.1010452.ref003","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ymben.2018.04.013","article-title":"Engineering a short, aldolase-based pathway for (R)-1,3-butanediol production in Escherichia coli","volume":"48","author":"K Nemr","year":"2018","journal-title":"Metab Eng"},{"key":"pcbi.1010452.ref004","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.copbio.2017.12.012","article-title":"Advances in gap-filling genome-scale metabolic models and model-driven experiments lead to novel metabolic discoveries","volume":"51","author":"S Pan","year":"2018","journal-title":"Curr Opin Biotechnol"},{"issue":"1","key":"pcbi.1010452.ref005","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nprot.2009.203","article-title":"A protocol for generating a high-quality genome-scale metabolic reconstruction","volume":"5","author":"I Thiele","year":"2010","journal-title":"Nat Protoc"},{"issue":"3","key":"pcbi.1010452.ref006","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1073\/pnas.1414218112","article-title":"Model-driven discovery of underground metabolic functions in Escherichia coli","volume":"112","author":"GI Guzman","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"pcbi.1010452.ref007","doi-asserted-by":"crossref","first-page":"7542","DOI":"10.1093\/nar\/gky537","article-title":"Fast automated reconstruction of genome-scale metabolic models for microbial species and communities","volume":"46","author":"D Machado","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"22","key":"pcbi.1010452.ref008","doi-asserted-by":"crossref","first-page":"6633","DOI":"10.1093\/nar\/gkg847","article-title":"Enzyme-specific profiles for genome annotation: PRIAM","volume":"31","author":"C Claudel-Renard","year":"2003","journal-title":"Nucleic Acids Res"},{"issue":"9","key":"pcbi.1010452.ref009","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/nbt.1672","article-title":"High-throughput generation, optimization and analysis of genome-scale metabolic models","volume":"28","author":"CS Henry","year":"2010","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pcbi.1010452.ref010","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1093\/nar\/28.1.304","article-title":"The ENZYME database in 2000","volume":"28","author":"A. Bairoch","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010452.ref011","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"SF Altschul","year":"1990","journal-title":"Journal of Molecular Biology"},{"issue":"1","key":"pcbi.1010452.ref012","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nmeth.3176","article-title":"Fast and sensitive protein alignment using DIAMOND","volume":"12","author":"B Buchfink","year":"2015","journal-title":"Nature Methods"},{"issue":"14","key":"pcbi.1010452.ref013","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1093\/bioinformatics\/btq266","article-title":"DETECT\u2014a density estimation tool for enzyme classification and its application to Plasmodium falciparum","volume":"26","author":"SS Hung","year":"2010","journal-title":"Bioinformatics"},{"issue":"19","key":"pcbi.1010452.ref014","doi-asserted-by":"crossref","first-page":"3393","DOI":"10.1093\/bioinformatics\/bty368","article-title":"Improved enzyme annotation with EC-specific cutoffs using DETECT v2","volume":"34","author":"N Nursimulu","year":"2018","journal-title":"Bioinformatics"},{"issue":"5","key":"pcbi.1010452.ref015","doi-asserted-by":"crossref","DOI":"10.1142\/S0219720015430039","article-title":"ENZDP: Improved enzyme annotation for metabolic network reconstruction based on domain composition profiles","volume":"13","author":"NN Nguyen","year":"2015","journal-title":"Journal of Bioinformatics and Computational Biology"},{"issue":"8","key":"pcbi.1010452.ref016","doi-asserted-by":"crossref","first-page":"e9110","DOI":"10.15252\/msb.20199110","article-title":"SBML Level 3: an extensible format for the exchange and reuse of biological models","volume":"16","author":"SM Keating","year":"2020","journal-title":"Mol Syst Biol"},{"key":"pcbi.1010452.ref017","doi-asserted-by":"crossref","first-page":"D191","DOI":"10.1093\/nar\/gku469","article-title":"Activities at the Universal Protein Resource (UniProt)","volume":"42","author":"The UniProt Consortium","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010452.ref018","doi-asserted-by":"crossref","first-page":"96","DOI":"10.3389\/fmolb.2018.00096","article-title":"Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism Caenorhabditis elegans","volume":"5","author":"M Witting","year":"2018","journal-title":"Front Mol Biosci"},{"key":"pcbi.1010452.ref019","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2011-12-12-r127","article-title":"Interrogation of global mutagenesis data with a genome scale model of Neisseria meningitidis","volume":"12","author":"TA Mendum","year":"2011","journal-title":"Genome Biology"},{"issue":"10","key":"pcbi.1010452.ref020","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/nbt.3956","article-title":"iML1515, a knowledgebase that computes Escherichia coli traits","volume":"35","author":"JM Monk","year":"2017","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pcbi.1010452.ref021","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1145\/2723872.2723882","article-title":"An introduction to Docker for reproducible research","volume":"49","author":"C. Boettiger","year":"2015","journal-title":"ACM SIGOPS Operating Systems Review"},{"issue":"11","key":"pcbi.1010452.ref022","doi-asserted-by":"crossref","first-page":"e1008316","DOI":"10.1371\/journal.pcbi.1008316","article-title":"Ten simple rules for writing Dockerfiles for reproducible data science","volume":"16","author":"D Nust","year":"2020","journal-title":"PLoS Comput Biol"},{"issue":"2","key":"pcbi.1010452.ref023","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/prot.22167","article-title":"Genome-wide enzyme annotation with precision control: catalytic families (CatFam) databases","volume":"74","author":"C Yu","year":"2009","journal-title":"Proteins"},{"issue":"20","key":"pcbi.1010452.ref024","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1093\/bioinformatics\/bts510","article-title":"EFICAz2.5: application of a high-precision enzyme function predictor to 396 proteomes","volume":"28","author":"N Kumar","year":"2012","journal-title":"Bioinformatics"},{"issue":"28","key":"pcbi.1010452.ref025","doi-asserted-by":"crossref","first-page":"13996","DOI":"10.1073\/pnas.1821905116","article-title":"Deep learning enables high-quality and high-throughput prediction of enzyme commission numbers","volume":"116","author":"JY Ryu","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"D1","key":"pcbi.1010452.ref026","doi-asserted-by":"crossref","first-page":"D545","DOI":"10.1093\/nar\/gkaa970","article-title":"KEGG: integrating viruses and cellular organisms","volume":"49","author":"M Kanehisa","year":"2021","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1010452.ref027","doi-asserted-by":"crossref","first-page":"D515","DOI":"10.1093\/nar\/gkv1049","article-title":"BiGG Models: A platform for integrating, standardizing and sharing genome-scale models","volume":"44","author":"ZA King","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010452.ref028","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1186\/1471-2105-7-436","article-title":"ORENZA: a web resource for studying ORphan ENZyme activities","volume":"7","author":"O Lespinet","year":"2006","journal-title":"BMC Bioinformatics"},{"issue":"12","key":"pcbi.1010452.ref029","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.pt.2009.09.006","article-title":"The global cysteine peptidase landscape in parasites","volume":"25","author":"HJ Atkinson","year":"2009","journal-title":"Trends Parasitol"},{"issue":"3","key":"pcbi.1010452.ref030","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.mib.2010.03.003","article-title":"The biomass objective function","volume":"13","author":"AM Feist","year":"2010","journal-title":"Curr Opin Microbiol"},{"issue":"7","key":"pcbi.1010452.ref031","doi-asserted-by":"crossref","first-page":"R136","DOI":"10.1186\/gb-2007-8-7-r136","article-title":"Modeling Neisseria meningitidis metabolism: from genome to metabolic fluxes","volume":"8","author":"GJ Baart","year":"2007","journal-title":"Genome Biol"},{"issue":"3","key":"pcbi.1010452.ref032","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1111\/j.1365-2958.2005.04866.x","article-title":"The pathogen Neisseria meningitidis requires oxygen, but supplements growth by denitrification. Nitrite, nitric oxide and oxygen control respiratory flux at genetic and metabolic levels","volume":"58","author":"JD Rock","year":"2005","journal-title":"Mol Microbiol"},{"key":"pcbi.1010452.ref033","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/msb4100155","article-title":"A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information","volume":"3","author":"AM Feist","year":"2007","journal-title":"Mol Syst Biol"},{"issue":"3","key":"pcbi.1010452.ref034","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/s41587-020-0446-y","article-title":"MEMOTE for standardized genome-scale metabolic model testing","volume":"38","author":"C Lieven","year":"2020","journal-title":"Nat Biotechnol"},{"issue":"D1","key":"pcbi.1010452.ref035","first-page":"D402","article-title":"BiGG Models 2020: multi-strain genome-scale models and expansion across the phylogenetic tree","volume":"48","author":"CJ Norsigian","year":"2020","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pcbi.1010452.ref036","doi-asserted-by":"crossref","first-page":"e1005494","DOI":"10.1371\/journal.pcbi.1005494","article-title":"Erroneous energy-generating cycles in published genome scale metabolic networks: Identification and removal","volume":"13","author":"CJ Fritzemeier","year":"2017","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010452.ref037","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1186\/s12864-016-2887-8","article-title":"Modeling central metabolism and energy biosynthesis across microbial life","volume":"17","author":"JN Edirisinghe","year":"2016","journal-title":"BMC Genomics"},{"issue":"1","key":"pcbi.1010452.ref038","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1186\/s12864-018-5221-9","article-title":"Combining multiple functional annotation tools increases coverage of metabolic annotation","volume":"19","author":"M Griesemer","year":"2018","journal-title":"BMC Genomics"},{"issue":"D1","key":"pcbi.1010452.ref039","doi-asserted-by":"crossref","first-page":"D543","DOI":"10.1093\/nar\/gkw1003","article-title":"The EcoCyc database: reflecting new knowledge about Escherichia coli K-12","volume":"45","author":"IM Keseler","year":"2017","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1010452.ref040","doi-asserted-by":"crossref","first-page":"D457","DOI":"10.1093\/nar\/gkv1070","article-title":"KEGG as a reference resource for gene and protein annotation","volume":"44","author":"M Kanehisa","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010452.ref041","doi-asserted-by":"crossref","first-page":"D206","DOI":"10.1093\/nar\/gkt1226","article-title":"The SEED and the Rapid Annotation of microbial genomes using Subsystems Technology (RAST)","volume":"42","author":"R Overbeek","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1010452.ref042","doi-asserted-by":"crossref","first-page":"D380","DOI":"10.1093\/nar\/gkw952","article-title":"BRENDA in 2017: new perspectives and new tools in BRENDA","volume":"45","author":"S Placzek","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010452.ref043","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gku1068","article-title":"BRENDA in 2015: exciting developments in its 25th year of existence","volume":"43","author":"A Chang","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"376","key":"pcbi.1010452.ref044","article-title":"EnzymeDetector: an integrated enzyme function prediction tool and database","volume":"12","author":"S Quester","year":"2011","journal-title":"BMC Bioinformatics"},{"issue":"2","key":"pcbi.1010452.ref045","doi-asserted-by":"crossref","first-page":"e0147952","DOI":"10.1371\/journal.pone.0147952","article-title":"Characterising Complex Enzyme Reaction Data","volume":"11","author":"HM Donertas","year":"2016","journal-title":"PLoS One"},{"issue":"2\u20133","key":"pcbi.1010452.ref046","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bpc.2009.08.007","article-title":"Quantitative assignment of reaction directionality in constraint-based models of metabolism: application to Escherichia coli","volume":"145","author":"RM Fleming","year":"2009","journal-title":"Biophys Chem"},{"key":"pcbi.1010452.ref047","volume-title":"Enzyme Nomenclature","author":"NC-IUBMB","year":"1992"},{"key":"pcbi.1010452.ref048","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/978-3-642-23808-6_10","article-title":"On the Stratification of Multi-label Data. Machine Learning and Knowledge Discovery in Databases","author":"K Sechidis","year":"2011","journal-title":"Lecture Notes in Computer Science"},{"issue":"114","key":"pcbi.1010452.ref049","article-title":"Solving gap metabolites and blocked reactions in genome-scale models: application to the metabolic network of Blattabacterium cuenoti","volume":"7","author":"M Ponce-de-Le\u00f3n","year":"2013","journal-title":"BMC Syst Biol"},{"issue":"D1","key":"pcbi.1010452.ref050","doi-asserted-by":"crossref","first-page":"D869","DOI":"10.1093\/nar\/gkx998","article-title":"WormBase 2017: molting into a new stage","volume":"46","author":"RYN Lee","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1010452.ref051","doi-asserted-by":"crossref","first-page":"D884","DOI":"10.1093\/nar\/gkaa942","article-title":"Ensembl 2021","volume":"49","author":"KL Howe","year":"2021","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pcbi.1010452.ref052","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.ipm.2009.03.002","article-title":"A systematic analysis of performance measures for classification tasks","volume":"45","author":"M Sokolova","year":"2009","journal-title":"Information Processing & Management"},{"issue":"3","key":"pcbi.1010452.ref053","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41596-018-0098-2","article-title":"Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0","volume":"14","author":"L Heirendt","year":"2019","journal-title":"Nat Protoc"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010452","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010452","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T14:06:17Z","timestamp":1663682777000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010452"}},"subtitle":[],"editor":[{"given":"Costas D.","family":"Maranas","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":53,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010452","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]}}}