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dc.contributor.authorAlmonacid, Daniel E.
dc.contributor.authorYera, Emmanuel R.
dc.contributor.authorMitchell, John B. O.
dc.contributor.authorBabbitt, Patricia C.
dc.date.accessioned2012-06-28T12:01:03Z
dc.date.available2012-06-28T12:01:03Z
dc.date.issued2010-03-12
dc.identifier.citationAlmonacid , D E , Yera , E R , Mitchell , J B O & Babbitt , P C 2010 , ' Quantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes : implications for classification of enzyme function ' , PLoS Computational Biology , vol. 6 , no. 3 , e1000700 . https://doi.org/10.1371/journal.pcbi.1000700en
dc.identifier.issn1553-734X
dc.identifier.otherPURE: 3442106
dc.identifier.otherPURE UUID: ed62f8b3-fc11-4924-8f2b-1854a835b534
dc.identifier.otherWOS: 000278125200008
dc.identifier.otherScopus: 77950855514
dc.identifier.otherORCID: /0000-0002-0379-6097/work/34033408
dc.identifier.urihttps://hdl.handle.net/10023/2866
dc.descriptionThe authors thank the National Institutes of Health (NIH R01 GM60595 to PCB) and the Scottish Universities Life Sciences Alliance (SULSA to JBOM) for funding.en
dc.description.abstractFunctionally analogous enzymes are those that catalyze similar reactions on similar substrates but do not share common ancestry, providing a window on the different structural strategies nature has used to evolve required catalysts. Identification and use of this information to improve reaction classification and computational annotation of enzymes newly discovered in the genome projects would benefit from systematic determination of reaction similarities. Here, we quantified similarity in bond changes for overall reactions and catalytic mechanisms for 95 pairs of functionally analogous enzymes (non-homologous enzymes with identical first three numbers of their EC codes) from the MACiE database. Similarity of overall reactions was computed by comparing the sets of bond changes in the transformations from substrates to products. For similarity of mechanisms, sets of bond changes occurring in each mechanistic step were compared; these similarities were then used to guide global and local alignments of mechanistic steps. Using this metric, only 44% of pairs of functionally analogous enzymes in the dataset had significantly similar overall reactions. For these enzymes, convergence to the same mechanism occurred in 33% of cases, with most pairs having at least one identical mechanistic step. Using our metric, overall reaction similarity serves as an upper bound for mechanistic similarity in functional analogs. For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity. By contrast, the three carboxylic-ester hydrolases (EC 3.1.1) catalyze overall reactions with identical bond changes and have converged to almost identical mechanisms. The large proportion of enzyme pairs that do not show significant overall reaction similarity (56%) suggests that at least for the functionally analogous enzymes studied here, more stringent criteria could be used to refine definitions of EC sub-subclasses for improved discrimination in their classification of enzyme reactions. The results also indicate that mechanistic convergence of reaction steps is widespread, suggesting that quantitative measurement of mechanistic similarity can inform approaches for functional annotation.
dc.format.extent18
dc.language.isoeng
dc.relation.ispartofPLoS Computational Biologyen
dc.rights© 2010 Almonacid et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectPyruvate formate-lyaseen
dc.subjectNh3-dependent nad(+) synthetaseen
dc.subjectProtein-tyrosine-phosphataseen
dc.subjectInverse sequence similarityen
dc.subjectGenome-scale classificationen
dc.subjectPlatelet-activating-factoren
dc.subjectUDP-N-acetylglucosamineen
dc.subjectEscherichia-colien
dc.subjectCrystal-structureen
dc.subjectQD Chemistryen
dc.subject.lccQDen
dc.titleQuantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes : implications for classification of enzyme functionen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1000700
dc.description.statusPeer revieweden
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=77950855514&partnerID=8YFLogxKen
dc.identifier.urlhttp://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000700en


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