{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T14:52:29Z","timestamp":1776610349323,"version":"3.51.2"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Enzyme promiscuity, a property with practical applications in biotechnology and synthetic biology, has been related to the evolvability of enzymes. At the molecular level, several structural mechanisms have been linked to enzyme promiscuity in enzyme families. However, it is at present unclear to what extent these observations can be generalized. Here, we introduce for the first time a method for predicting catalytic and substrate promiscuity using a graph-based representation known as molecular signature.<\/jats:p><jats:p>Results: Our method, which has an accuracy of 85% for the non-redundant KEGG database, is also a powerful analytical tool for characterizing structural determinants of protein promiscuity. Namely, we found that signatures with higher contribution to the prediction of promiscuity are uniformly distributed in the protein structure of promiscuous enzymes. In contrast, those signatures that act as promiscuity determinants are significantly depleted around non-promiscuous catalytic sites. In addition, we present the study of the enolase and aminotransferase superfamilies as illustrative examples of characterization of promiscuous enzymes within a superfamily and achievement of enzyme promiscuity by protein reverse engineering. Recognizing the role of enzyme promiscuity in the process of natural evolution of enzymatic function can provide useful hints in the design of directed evolution experiments. We have developed a method with potential applications in the guided discovery and enhancement of latent catalytic capabilities surviving in modern enzymes.<\/jats:p><jats:p>Availability: \u00a0http:\/\/www.issb.genopole.fr\u223cfaulon<\/jats:p><jats:p>Contact: \u00a0pcarbonell@issb.genopole.fr<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btq317","type":"journal-article","created":{"date-parts":[[2010,6,16]],"date-time":"2010-06-16T01:09:58Z","timestamp":1276650598000},"page":"2012-2019","source":"Crossref","is-referenced-by-count":70,"title":["Molecular signatures-based prediction of enzyme promiscuity"],"prefix":"10.1093","volume":"26","author":[{"given":"Pablo","family":"Carbonell","sequence":"first","affiliation":[{"name":"iSSB, Institute of Systems and Synthetic Biology, University of Evry, Genopole Campus 1, Genavenir 6, 5 rue Henri Desbru\u00e8res, 91030 EVRY Cedex, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Loup","family":"Faulon","sequence":"additional","affiliation":[{"name":"iSSB, Institute of Systems and Synthetic Biology, University of Evry, Genopole Campus 1, Genavenir 6, 5 rue Henri Desbru\u00e8res, 91030 EVRY Cedex, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2010,6,15]]},"reference":[{"key":"2023012508021271400_B1","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":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"2023012508021271400_B2","doi-asserted-by":"crossref","first-page":"5303","DOI":"10.1021\/bi9923813","article-title":"Recruitment of a double bond isomerase to serve as a reductive dehalogenase during biodegradation of pentachlorophenol","volume":"39","author":"Anandarajah","year":"2000","journal-title":"Biochemistry"},{"key":"2023012508021271400_B3","doi-asserted-by":"crossref","first-page":"msb4100073\u2013E1","DOI":"10.1038\/msb4100073","article-title":"Synthetic biology: new engineering rules for an emerging discipline","volume":"2","author":"Andrianantoandro","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"2023012508021271400_B4","doi-asserted-by":"crossref","first-page":"16489","DOI":"10.1021\/bi9616413","article-title":"The enolase superfamily: A general strategy for enzyme-catalyzed abstraction of the protons of carboxylic acids","volume":"35","author":"Babbitt","year":"1996","journal-title":"Biochemistry"},{"key":"2023012508021271400_B5","doi-asserted-by":"crossref","first-page":"5144","DOI":"10.1128\/jb.173.16.5144-5150.1991","article-title":"L-lyxose metabolism employs the L-rhamnose pathway in mutant cells of Escherichia coli adapted to grow on L-lyxose","volume":"173","author":"Badia","year":"1991","journal-title":"J. Bacteriol."},{"key":"2023012508021271400_B6","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0022-2836(02)01036-7","article-title":"Analysis of catalytic residues in enzyme active sites","volume":"324","author":"Bartlett","year":"2002","journal-title":"J. Mol. Biol."},{"key":"2023012508021271400_B7","doi-asserted-by":"crossref","first-page":"6032","DOI":"10.1002\/anie.200460416","article-title":"Catalytic promiscuity in biocatalysis: using old enzymes to form new bonds and follow new pathways","volume":"43","author":"Bornscheuer","year":"2004","journal-title":"Angew. Chem. Int. Ed"},{"key":"2023012508021271400_B8","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1002\/pmic.200800425","article-title":"Energetic determinants of protein binding specificity: insights into protein interaction networks","volume":"9","author":"Carbonell","year":"2009","journal-title":"Proteomics"},{"key":"2023012508021271400_B9","doi-asserted-by":"crossref","first-page":"gkn820","DOI":"10.1093\/nar\/gkn820","article-title":"Brenda, amenda and frenda the enzyme information system: new content and tools in 2009","volume":"37","author":"Chang","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012508021271400_B10","doi-asserted-by":"crossref","first-page":"9608","DOI":"10.1021\/bi800821v","article-title":"Structural basis for substrate specificity in phosphate binding (beta\/alpha)8-barrels: D-allulose 6-phosphate 3-epimerase from Escherichia coli k-12","volume":"47","author":"Chan","year":"2008","journal-title":"Biochemistry"},{"key":"2023012508021271400_B11","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S1367-5931(03)00032-2","article-title":"Enzymes with extra talents: moonlighting functions and catalytic promiscuity","volume":"7","author":"Copley","year":"2003","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2023012508021271400_B12","volume-title":"The PyMOL User's Manual.","author":"Delano","year":"2002"},{"key":"2023012508021271400_B13","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1021\/ci0341823","article-title":"The signature molecular descriptor. 4. canonizing molecules using extended valence sequences","volume":"44","author":"Faulon","year":"2004","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"2023012508021271400_B14","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/bioinformatics\/btm580","article-title":"Genome scale enzyme metabolite and drug target interaction predictions using the signature molecular descriptor","volume":"24","author":"Faulon","year":"2008","journal-title":"Bioinformatics"},{"key":"2023012508021271400_B15","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/978-3-540-45167-9_11","article-title":"On graph kernels: Hardness results and efficient alternatives","volume":"2777","author":"Gartner","year":"2003","journal-title":"Lect. Notes Comput. Sci."},{"key":"2023012508021271400_B16","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.jmb.2006.04.055","article-title":"Evolution of structure and function in the o-succinylbenzoate synthase\/n-acylamino acid racemase family of the enolase superfamily","volume":"360","author":"Glasner","year":"2006","journal-title":"J. Mol. Biol."},{"key":"2023012508021271400_B17","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1093\/bioinformatics\/btg111","article-title":"Do current sequence analysis algorithms disclose multifunctional (moonlighting) proteins?","volume":"19","author":"Gomez","year":"2003","journal-title":"Bioinformatics"},{"key":"2023012508021271400_B18","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1023\/A:1012487302797","article-title":"Gene selection for cancer classification using support vector machines","volume":"46","author":"Guyon","year":"2002","journal-title":"Mach. Learn."},{"key":"2023012508021271400_B19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1006\/jmbi.1999.2661","article-title":"The relationship between protein structure and function: a comprehensive survey with application to the yeast genome","volume":"288","author":"Hegyi","year":"1999","journal-title":"J. Mol. Biol."},{"issue":"5","key":"2023012508021271400_B20","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.tibtech.2007.03.002","article-title":"Enzyme promiscuity: mechanism and applications","volume":"25","author":"Hult","year":"2007","journal-title":"Trends Biotechnol."},{"key":"2023012508021271400_B21","doi-asserted-by":"crossref","first-page":"18939","DOI":"10.1074\/jbc.275.25.18939","article-title":"Free energy requirement for domain movement of an enzyme","volume":"275","author":"Ishijima","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2023012508021271400_B22","doi-asserted-by":"crossref","first-page":"9925","DOI":"10.1073\/pnas.160255397","article-title":"Directed evolution of a (alpha-beta)8-barrel enzyme to catalyze related reactions in two different metabolic pathways","volume":"97","author":"Jurgens","year":"2000","journal-title":"Proc. Natl Acad. USA"},{"key":"2023012508021271400_B23","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"key":"2023012508021271400_B24","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkm882","article-title":"KEGG for linking genomes to life and the environment","volume":"36","author":"Kanehisa","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"2023012508021271400_B25","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.cbpa.2005.02.008","article-title":"Enhancing catalytic promiscuity for biocatalysis","volume":"9","author":"Kazlauskas","year":"2005","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2023012508021271400_B26","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.cbpa.2006.08.011","article-title":"Enzyme promiscuity: evolutionary and mechanistic aspects","volume":"10","author":"Khersonsky","year":"2006","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2023012508021271400_B27","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/msb.2008.16","article-title":"The role of disorder in interaction networks: a structural analysis","volume":"4","author":"Kim","year":"2008","journal-title":"Mol. Syst. Biol."},{"key":"2023012508021271400_B28","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/sj.embor.7400330","article-title":"Two-fold repeated (betaalpha)4 half-barrels may provide a molecular tool for dual substrate specificity","volume":"6","author":"Kuper","year":"2005","journal-title":"EMBO Rep."},{"key":"2023012508021271400_B29","first-page":"1441","article-title":"Mismatch string kernels for SVM protein classification","volume-title":"Advances in Neural Information Processing Systems 15.","author":"Leslie","year":"2003"},{"key":"2023012508021271400_B30","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.str.2003.10.002","article-title":"Protein disorder prediction: implications for structural proteomics","volume":"11","author":"Linding","year":"2003","journal-title":"Structure"},{"key":"2023012508021271400_B31","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1093\/bioinformatics\/btl158","article-title":"Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences","volume":"22","author":"Li","year":"2006","journal-title":"Bioinformatics"},{"key":"2023012508021271400_B32","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/nbt999","article-title":"Ligand selectivity and competition between enzymes in silico","volume":"22","author":"Macchiarulo","year":"2004","journal-title":"Nat. Biotechnol."},{"key":"2023012508021271400_B33","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1093\/bioinformatics\/bth483","article-title":"Predicting protein-protein interactions using signature products","volume":"21","author":"Martin","year":"2005","journal-title":"Bioinformatics"},{"key":"2023012508021271400_B34","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1529\/biophysj.104.057158","article-title":"Specificity of trypsin and chymotrypsin: loop-motion-controlled dynamic correlation as a determinant","volume":"89","author":"Ma","year":"2005","journal-title":"Biophys. J."},{"key":"2023012508021271400_B35","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/S0022-2836(05)80134-2","article-title":"SCOP: a structural classification of proteins database for the investigation of sequences and structures","volume":"247","author":"Murzin","year":"1995","journal-title":"J. Mol. Biol."},{"key":"2023012508021271400_B36","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nbt1519","article-title":"Protein promiscuity and its implications for biotechnology","volume":"27","author":"Nobeli","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"2023012508021271400_B37","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S1074-5521(99)80033-7","article-title":"Catalytic promiscuity and the evolution of new enzymatic activities","volume":"6","author":"O'Brien","year":"1999","journal-title":"Chem. Biol."},{"key":"2023012508021271400_B38","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/S0969-2126(97)00260-8","article-title":"CATH\u2014a hierarchic classification of protein domain structures","volume":"5","author":"Orengo","year":"1997","journal-title":"Structure"},{"key":"2023012508021271400_B39","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/35001176","article-title":"Enzyme evolution: design by necessity","volume":"403","author":"Petsko","year":"2000","journal-title":"Nature"},{"key":"2023012508021271400_B40","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1007\/s00018-008-8285-x","article-title":"The chemical versatility of the fold: catalytic promiscuity and divergent evolution in the tautomerase superfamily","volume":"65","author":"Poelarends","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"issue":"Suppl. 1","key":"2023012508021271400_B41","doi-asserted-by":"crossref","first-page":"D129","DOI":"10.1093\/nar\/gkh028","article-title":"The catalytic site atlas: a resource of catalytic sites and residues identified in enzymes using structural data","volume":"32","author":"Porter","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023012508021271400_B42","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/nrm2805","article-title":"Exploring protein fitness landscapes by directed evolution","volume":"10","author":"Romero","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023012508021271400_B43","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S0022-2836(03)00095-0","article-title":"How does an enzyme evolved in vitro compare to naturally occurring homologs possessing the targeted function? tyrosine aminotransferase from aspartate aminotransferase","volume":"327","author":"Rothman","year":"2003","journal-title":"J. Mol. Biol."},{"key":"2023012508021271400_B44","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1093\/bioinformatics\/bth141","article-title":"Protein homology detection using string alignment kernels","volume":"20","author":"Saigo","year":"2004","journal-title":"Bioinformatics"},{"key":"2023012508021271400_B45","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1472-6807-7-3","article-title":"Occurrence of protein structure elements in conserved sequence regions","volume":"7","author":"Sitbon","year":"2007","journal-title":"BMC Struc. Biol."},{"key":"2023012508021271400_B46","doi-asserted-by":"crossref","first-page":"8597","DOI":"10.1002\/anie.200702751","article-title":"Alternate-site enzyme promiscuity","volume":"46","author":"Taglieber","year":"2007","journal-title":"Angewandte Chemie"},{"key":"2023012508021271400_B47","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1002\/pro.181","article-title":"Exploring functional roles of multibinding protein interfaces","volume":"18","author":"Tyagi","year":"2009","journal-title":"Protein Sci."},{"key":"2023012508021271400_B48","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4757-2440-0","volume-title":"The nature of statistical learning theory.","author":"Vapnik","year":"1995"},{"key":"2023012508021271400_B49","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1002\/pro.11","article-title":"Structural modification of acyl carrier protein by butyryl group","volume":"18","author":"Wu","year":"2009","journal-title":"Protein Sci."},{"key":"2023012508021271400_B50","doi-asserted-by":"crossref","first-page":"5511","DOI":"10.1073\/pnas.95.10.5511","article-title":"Directed evolution of an aspartate aminotransferase with new substrate specificities","volume":"95","author":"Yano","year":"1998","journal-title":"Proc. Natl Acad. USA"},{"key":"2023012508021271400_B51","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jmb.2004.09.035","article-title":"Crystal structure of the pyrococcus horikoshii isopropylmalate isomerase small subunit provides insight into the dual substrate specificity of the enzyme","volume":"344","author":"Yasutake","year":"2004","journal-title":"J. Mol. Biol."},{"key":"2023012508021271400_B52","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/nature04607","article-title":"Designed divergent evolution of enzyme function","volume":"440","author":"Yoshikuni","year":"2006","journal-title":"Nature"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/26\/16\/2012\/48853474\/bioinformatics_26_16_2012.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/26\/16\/2012\/48853474\/bioinformatics_26_16_2012.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T16:30:38Z","timestamp":1711557038000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/26\/16\/2012\/215921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,6,15]]},"references-count":52,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2010,8,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btq317","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2010,8,15]]},"published":{"date-parts":[[2010,6,15]]}}}