title: Large-Scale Analysis Exploring Evolution of Catalytic Machineries and Mechanisms in Enzyme Superfamilies.
abstract: Enzymes, as biological catalysts, form the basis of all forms of life. How these proteins have evolved their functions remains a fundamental question in biology. Over 100 years of detailed biochemistry studies, combined with the large volumes of sequence and protein structural data now available, means that we are able to perform large-scale analyses to address this question. Using a range of computational tools and resources, we have compiled information on all experimentally annotated changes in enzyme function within 379 structurally defined protein domain superfamilies, linking the changes observed in functions during evolution to changes in reaction chemistry. Many superfamilies show changes in function at some level, although one function often dominates one superfamily. We use quantitative measures of changes in reaction chemistry to reveal the various types of chemical changes occurring during evolution and to exemplify these by detailed examples. Additionally, we use structural information of the enzymes active site to examine how different superfamilies have changed their catalytic machinery during evolution. Some superfamilies have changed the reactions they perform without changing catalytic machinery. In others, large changes of enzyme function, in terms of both overall chemistry and substrate specificity, have been brought about by significant changes in catalytic machinery. Interestingly, in some superfamilies, relatives perform similar functions but with different catalytic machineries. This analysis highlights characteristics of functional evolution across a wide range of superfamilies, providing insights that will be useful in predicting the function of uncharacterised sequences and the design of new synthetic enzymes.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Furnham
authors.affiliation: Institute of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Dawson
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Rahman
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Thornton
authors.affiliation: Institute of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Orengo
mesh_terms: D020134:Catalytic Domain; D019295:Computational Biology; D019143:Evolution, Molecular; D006867:Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular
chemical_list: D006867:Hydrolases
keywords: catalytic residues; enzyme function evolution; enzyme reaction chemistry; protein domain evolution; protein domain superfamilies