{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T19:23:54Z","timestamp":1774121034444,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2017,7,27]],"date-time":"2017-07-27T00:00:00Z","timestamp":1501113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"funder":[{"DOI":"10.13039\/501100003845","name":"Indian Institute of Technology Madras","doi-asserted-by":"publisher","award":["CSE\/14-15\/5643\/NFSC\/SAYN"],"award-info":[{"award-number":["CSE\/14-15\/5643\/NFSC\/SAYN"]}],"id":[{"id":"10.13039\/501100003845","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>The ability to predict pathways for biosynthesis of metabolites is very important in metabolic engineering. It is possible to mine the repertoire of biochemical transformations from reaction databases, and apply the knowledge to predict reactions to synthesize new molecules. However, this usually involves a careful understanding of the mechanism and the knowledge of the exact bonds being created and broken. There is a need for a method to rapidly predict reactions for synthesizing new molecules, which relies only on the structures of the molecules, without demanding additional information such as thermodynamics or hand-curated reactant mapping, which are often hard to obtain accurately.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We here describe a robust method based on subgraph mining, to predict a series of biochemical transformations, which can convert between two (even previously unseen) molecules. We first describe a reliable method based on subgraph edit distance to map reactants and products, using only their chemical structures. Having mapped reactants and products, we identify the reaction centre and its neighbourhood, the reaction signature, and store this in a reaction rule network. This novel representation enables us to rapidly predict pathways, even between previously unseen molecules. We demonstrate this ability by predicting pathways to molecules not present in the KEGG database. We also propose a heuristic that predominantly recovers natural biosynthetic pathways from amongst hundreds of possible alternatives, through a directed search of the reaction rule network, enabling us to provide a reliable ranking of the different pathways. Our approach scales well, even to databases with &amp;gt;100\u2009000 reactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>A Java-based implementation of our algorithms is available at https:\/\/github.com\/RamanLab\/ReactionMiner.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btx481","type":"journal-article","created":{"date-parts":[[2017,7,26]],"date-time":"2017-07-26T13:40:04Z","timestamp":1501076404000},"page":"3955-3963","source":"Crossref","is-referenced-by-count":18,"title":["Predicting novel metabolic pathways through subgraph mining"],"prefix":"10.1093","volume":"33","author":[{"given":"Aravind","family":"Sankar","sequence":"first","affiliation":[{"name":"Department of Computer Science and Engineering, Indian Institute of Technology (IIT) Madras, Chennai, Tamil Nadu, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayan","family":"Ranu","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, Indian Institute of Technology (IIT) Madras, Chennai, Tamil Nadu, India"},{"name":"Initiative for Biological Systems Engineering (IBSE), Interdisciplinary Laboratory for Data Sciences, Indian Institute of Technology (IIT) Madras, Chennai, Tamil Nadu, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9311-7093","authenticated-orcid":false,"given":"Karthik","family":"Raman","sequence":"additional","affiliation":[{"name":"Initiative for Biological Systems Engineering (IBSE), Interdisciplinary Laboratory for Data Sciences, Indian Institute of Technology (IIT) Madras, Chennai, Tamil Nadu, India"},{"name":"Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology (IIT) Madras, Chennai, Tamil Nadu, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,7,27]]},"reference":[{"key":"2023020207504035200_btx481-B1","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1039\/C6MB00796A","article-title":"Elucidating the biosynthetic pathways of volatile organic compounds in Mycobacterium tuberculosis through a computational approach","volume":"13","author":"Bhatter","year":"2017","journal-title":"Mol. BioSyst"},{"key":"2023020207504035200_btx481-B2","doi-asserted-by":"crossref","first-page":"4672","DOI":"10.1128\/JB.184.17.4672-4680.2002","article-title":"Organization and regulation of pentachlorophenol-degrading genes in Sphingobium chlorophenolicum ATCC 39723","volume":"184","author":"Cai","year":"2002","journal-title":"J. Bacteriol"},{"key":"2023020207504035200_btx481-B3","doi-asserted-by":"crossref","first-page":"10+","DOI":"10.1186\/1752-0509-6-10","article-title":"Enumerating metabolic pathways for the production of heterologous target chemicals in chassis organisms","volume":"6","author":"Carbonell","year":"2012","journal-title":"BMC Syst. Biol"},{"key":"2023020207504035200_btx481-B4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1021\/sb4001273","article-title":"Retropath: automated pipeline for embedded metabolic circuits","volume":"3","author":"Carbonell","year":"2014","journal-title":"ACS Synth. Biol"},{"key":"2023020207504035200_btx481-B5","doi-asserted-by":"crossref","first-page":"W389","DOI":"10.1093\/nar\/gku362","article-title":"XTMS: pathway design in an eXTended metabolic space","volume":"42","author":"Carbonell","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023020207504035200_btx481-B6","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/1752-0509-5-122","article-title":"A retrosynthetic biology approach to metabolic pathway design for therapeutic production","volume":"5","author":"Carbonell","year":"2011","journal-title":"BMC Syst. Biol"},{"key":"2023020207504035200_btx481-B7","doi-asserted-by":"crossref","first-page":"D742","DOI":"10.1093\/nar\/gkr1014","article-title":"The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway\/genome databases","volume":"40","author":"Caspi","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2023020207504035200_btx481-B8","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1021\/ci900157k","article-title":"No electron left behind: a rule-based expert system to predict chemical reactions and reaction mechanisms","volume":"49","author":"Chen","year":"2009","journal-title":"J. Chem. Inf. Model"},{"key":"2023020207504035200_btx481-B9","doi-asserted-by":"crossref","first-page":"W129","DOI":"10.1093\/nar\/gkp264","article-title":"FMM: a web server for metabolic pathway reconstruction and comparative analysis","volume":"37","author":"Chou","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"2023020207504035200_btx481-B10","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nchembio.197","article-title":"Evolution of efficient pathways for degradation of anthropogenic chemicals","volume":"5","author":"Copley","year":"2009","journal-title":"Nat. Chem. Biol"},{"key":"2023020207504035200_btx481-B11","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1126\/science.166.3902.178","article-title":"Computer-assisted design of complex organic syntheses","volume":"166","author":"Corey","year":"1969","journal-title":"Science"},{"key":"2023020207504035200_btx481-B12","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1093\/bioinformatics\/btt036","article-title":"MetaNetX.org: a website and repository for accessing, analysing and manipulating metabolic networks","volume":"29","author":"Ganter","year":"2013","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B13","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1021\/acssynbio.6b00054","article-title":"ATLAS of biochemistry: a repository of all possible biochemical reactions for synthetic biology and metabolic engineering studies","volume":"5","author":"Hadadi","year":"2016","journal-title":"ACS Synth. Biol"},{"key":"2023020207504035200_btx481-B14","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.cbpa.2015.06.025","article-title":"Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways","volume":"28","author":"Hadadi","year":"2015","journal-title":"Curr. Opin. Chem. Biol"},{"key":"2023020207504035200_btx481-B15","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1093\/bioinformatics\/bti213","article-title":"Exploring the diversity of complex metabolic networks","volume":"21","author":"Hatzimanikatis","year":"2005","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B16","first-page":"38","author":"He","year":"2006"},{"key":"2023020207504035200_btx481-B17","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":"Kanehisa","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023020207504035200_btx481-B18","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1103\/RevModPhys.31.549","article-title":"Chemical specificity in biological systems","volume":"31","author":"Kauzmann","year":"1959","journal-title":"Rev. Mod. Phys"},{"key":"2023020207504035200_btx481-B19","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1021\/ci3003039","article-title":"ReactionPredictor: prediction of complex chemical reactions at the mechanistic level using machine learning","volume":"52","author":"Kayala","year":"2012","journal-title":"J. Chem. Inf. Model"},{"key":"2023020207504035200_btx481-B20","doi-asserted-by":"crossref","first-page":"i165.","DOI":"10.1093\/bioinformatics\/btu265","article-title":"Metabolome-scale prediction of intermediate compounds in multistep metabolic pathways with a recursive supervised approach","volume":"30","author":"Kotera","year":"2014","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B21","doi-asserted-by":"crossref","first-page":"i135","DOI":"10.1093\/bioinformatics\/btt244","article-title":"Supervised de novo reconstruction of metabolic pathways from metabolome-scale compound sets","volume":"29","author":"Kotera","year":"2013","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B22","doi-asserted-by":"crossref","first-page":"W217","DOI":"10.1093\/nar\/gkw342","article-title":"MRE: a web tool to suggest foreign enzymes for the biosynthesis pathway design with competing endogenous reactions in mind","volume":"44","author":"Kuwahara","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023020207504035200_btx481-B23","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1093\/bioinformatics\/btu150","article-title":"Optimal metabolic route search based on atom mappings","volume":"30","author":"Latendresse","year":"2014","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B24","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1002\/bit.260361107","article-title":"Computer-aided synthesis of biochemical pathways","volume":"36","author":"Mavrovouniotis","year":"1990","journal-title":"Biotechnol. Bioeng"},{"key":"2023020207504035200_btx481-B25","doi-asserted-by":"crossref","first-page":"e113.","DOI":"10.1093\/nar\/gkt234","article-title":"Metabolic tinker: an online tool for guiding the design of synthetic metabolic pathways","volume":"41","author":"McClymont","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2023020207504035200_btx481-B26","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nrmicro2717","article-title":"Computational tools for the synthetic design of biochemical pathways","volume":"10","author":"Medema","year":"2012","journal-title":"Nat. Rev. Microbiol"},{"key":"2023020207504035200_btx481-B27","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1093\/bioinformatics\/btp269","article-title":"Rahnuma: hypergraph-based tool for metabolic pathway prediction and network comparison","volume":"25","author":"Mithani","year":"2009","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B28","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nbt.2870","article-title":"Optimizing genome-scale network reconstructions","volume":"32","author":"Monk","year":"2014","journal-title":"Nat. Biotechnol"},{"key":"2023020207504035200_btx481-B29","doi-asserted-by":"crossref","first-page":"W138","DOI":"10.1093\/nar\/gkq318","article-title":"PathPred: an enzyme-catalyzed metabolic pathway prediction server","volume":"38","author":"Moriya","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2023020207504035200_btx481-B30","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.molcel.2010.08.031","article-title":"Central carbon metabolism as a minimal biochemical walk between precursors for biomass and energy","volume":"39","author":"Noor","year":"2010","journal-title":"Mol. Cell"},{"key":"2023020207504035200_btx481-B31","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1021\/ci700006f","article-title":"Systematic analysis of enzyme-catalyzed reaction patterns and prediction of microbial biodegradation pathways","volume":"47","author":"Oh","year":"2007","journal-title":"J. Chem. Inf. Model"},{"key":"2023020207504035200_btx481-B32","doi-asserted-by":"crossref","DOI":"10.1533\/9780857099921","volume-title":"Enzymes: Biochemistry, Biotechnology and Clinical Chemistry","author":"Palmer","year":"2007"},{"key":"2023020207504035200_btx481-B33","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1093\/bioinformatics\/bti116","article-title":"Metabolic pathway analysis web service (pathway hunter tool at cubic)","volume":"21","author":"Rahman","year":"2005","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B34","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nmeth.2803","article-title":"EC-BLAST: a tool to automatically search and compare enzyme reactions","volume":"11","author":"Rahman","year":"2014","journal-title":"Nat. Methods"},{"key":"2023020207504035200_btx481-B35","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1758-2946-1-12","article-title":"Small molecule subgraph detector (SMSD) toolkit","volume":"1","author":"Rahman","year":"2009","journal-title":"J. Cheminform"},{"key":"2023020207504035200_btx481-B36","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/nature04640","article-title":"Production of the antimalarial drug precursor artemisinic acid in engineered yeast","volume":"440","author":"Ro","year":"2006","journal-title":"Nature"},{"key":"2023020207504035200_btx481-B37","volume-title":"Graph Transformations","author":"Rossell\u00f3","year":"2004"},{"key":"2023020207504035200_btx481-B38","volume-title":"Artificial Intelligence: A Modern Approach","author":"Russell","year":"2003","edition":"2nd edn."},{"key":"2023020207504035200_btx481-B39","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1093\/bioinformatics\/btw491","article-title":"ReactPRED: a tool to predict and analyze biochemical reactions","volume":"32","author":"Sivakumar","year":"2016","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B40","author":"Werpy","year":"2004"},{"key":"2023020207504035200_btx481-B41","doi-asserted-by":"crossref","first-page":"i161","DOI":"10.1093\/bioinformatics\/btv224","article-title":"Metabolome-scale de novo pathway reconstruction using regioisomer-sensitive graph alignments","volume":"31","author":"Yamanishi","year":"2015","journal-title":"Bioinformatics"},{"key":"2023020207504035200_btx481-B42","doi-asserted-by":"crossref","first-page":"25","DOI":"10.14778\/1687627.1687631","article-title":"Comparing stars: on approximating graph edit distance","volume":"2","author":"Zeng","year":"2009","journal-title":"Proc. VLDB Endow"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/33\/24\/3955\/49041879\/bioinformatics_33_24_3955.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/33\/24\/3955\/49041879\/bioinformatics_33_24_3955.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T02:51:41Z","timestamp":1675306301000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/33\/24\/3955\/4042129"}},"subtitle":[],"editor":[{"given":"Oliver","family":"Stegle","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2017,7,27]]},"references-count":42,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2017,12,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btx481","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/123877","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,12,15]]},"published":{"date-parts":[[2017,7,27]]}}}