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REPRESENTING STRUCTURE-FUNCTION RELATIONSHIPS IN MECHANISTICALLY DIVERSE ENZYME SUPERFAMILIES

SCOTT C.-H. PEGG, SHOSHANA BROWN, SUNIL OJHA, CONRAD C. HUANG, THOMAS E. FERRIN, PATRICIA C. BABBITT
2004 Biocomputing 2005  
In the case of enzymes, the study of mechanistically diverse superfamilies can provide a rich source of structure-function information useful in functional determination and enzyme engineering.  ...  To access these relationships using a computational resource, several issues must be addressed regarding the representation of enzyme function, the organization of structure-function relationships in the  ...  Acknowledgments We thank John Gerlt for expert advice on the enolase and crotonase superfamilies, and Kinkead Reiling for his advice on the terpene cyclase superfamily.  ... 
doi:10.1142/9789812702456_0034 fatcat:zlnfepjmvbfkvgwzmw76ulakpu

Leveraging Enzyme Structure−Function Relationships for Functional Inference and Experimental Design: The Structure−Function Linkage Database†

Scott C.-H. Pegg, Shoshana D. Brown, Sunil Ojha, Jennifer Seffernick, Elaine C. Meng, John H. Morris, Patricia J. Chang, Conrad C. Huang, Thomas E. Ferrin, Patricia C. Babbitt
2006 Biochemistry  
residuesshelps elucidate the structure-function relationships of enzymes.  ...  The study of mechanistically diverse enzyme superfamiliesscollections of enzymes that perform different overall reactions but share both a common fold and a distinct mechanistic step performed by key conserved  ...  Specifically, the SFLD captures structure-function relationships in mechanistically diverse enzyme superfamilies.  ... 
doi:10.1021/bi052101l pmid:16489747 fatcat:dajbxfc4ajbq3hckmbou2ep2v4

Toward mechanistic classification of enzyme functions

Daniel E Almonacid, Patricia C Babbitt
2011 Current Opinion in Chemical Biology  
Here we describe how evolution informs these structure-function mappings and review the databases that store mechanisms of enzyme reactions along with recent developments to measure ligand and mechanistic  ...  Large-scale studies have established that divergently evolved enzymes share conserved elements of structure and common mechanistic steps and that convergently evolved enzymes often converge to similar  ...  The SFLD stores structure-function relationships for functionally diverse enzyme superfamilies at three levels of granularity: superfamilies, subgroups, and families.  ... 
doi:10.1016/j.cbpa.2011.03.008 pmid:21489855 pmcid:PMC3551611 fatcat:yy6jwgqljrc7bpotr5bwfhxiei

A gold standard set of mechanistically diverse enzyme superfamilies

Shoshana D Brown, John A Gerlt, Jennifer L Seffernick, Patricia C Babbitt
2006 Genome Biology  
We describe a 'gold standard' set of enzyme superfamilies, clustered according to specific sequence, structure, and functional criteria, for use in the validation of family and superfamily clustering methods  ...  The gold standard set represents four fold classes and differing clustering difficulties, and includes five superfamilies, 91 families, 4,887 sequences and 282 structures.  ...  Acknowledgements We thank Ranyee Chiang for analysis of SCOPEC to provide an estimate of the number of mechanistically diverse superfamilies that may exist.  ... 
doi:10.1186/gb-2006-7-1-r8 pmid:16507141 pmcid:PMC1431709 fatcat:dghqy7exyncfna6udyiqdn7gte

New Insights about Enzyme Evolution from Large Scale Studies of Sequence and Structure Relationships

Shoshana D. Brown, Patricia C. Babbitt
2014 Journal of Biological Chemistry  
Functionally (or mechanistically) diverse superfamilies are evolutionarily related sets of enzymes that may be quite diverse in sequence, structure, and overall reaction, but share a conserved constellation  ...  Functionally diverse superfamilies represent a significant proportion of the enzyme universe, making up more than onethird of all structurally characterized enzyme superfamilies (7) .  ...  Functionally (or mechanistically) diverse superfamilies are evolutionarily related sets of enzymes that may be quite diverse in sequence, structure, and overall reaction, but share a conserved constellation  ... 
doi:10.1074/jbc.r114.569350 pmid:25210038 pmcid:PMC4215206 fatcat:biiui2rljngshklchfp6465hom

Exploiting structural classifications for function prediction: towards a domain grammar for protein function

Benoît H Dessailly, Oliver C Redfern, Alison Cuff, Christine A Orengo
2009 Current Opinion in Structural Biology  
Here we discuss the extent to which structural domain classifications can help in deciphering the complex relationship between the functions of proteins and their sequences and structures.  ...  Structural classifications are particularly helpful in understanding the mosaic manner in which new proteins and functions emerge through evolution.  ...  Acknowledgements This work was supported by a grant from the Protein Structure Initiative (PSI) of the National Institute for General Medicine at the National Institutes of Health and by the European Union  ... 
doi:10.1016/j.sbi.2009.03.009 pmid:19398323 pmcid:PMC2920418 fatcat:4bs4xfd5nrb6hc2howuhmorjhi

Divergent Evolution of Enzymatic Function: Mechanistically Diverse Superfamilies and Functionally Distinct Suprafamilies

John A. Gerlt, Patricia C. Babbitt
2001 Annual Review of Biochemistry  
Groups of divergently related enzymes whose members catalyze different reactions but share a common partial reaction, intermediate, or transition state (mechanistically diverse superfamilies) have been  ...  Other groups of divergently related enzymes whose members catalyze different overall reactions that do not share a common mechanistic strategy (functionally distinct suprafamilies) have also been identified  ...  The old and new enzymes would be members of mechanistically diverse superfamilies.  ... 
doi:10.1146/annurev.biochem.70.1.209 pmid:11395407 fatcat:43mhvcfzbjglvjui474norb7z4

The evolution of enzyme function in the isomerases

Sergio Martinez Cuesta, Nicholas Furnham, Syed Asad Rahman, Ian Sillitoe, Janet M Thornton
2014 Current Opinion in Structural Biology  
This paper reviews research efforts aiming to understand the evolution of enzyme function in superfamilies, presenting a novel strategy to provide an overview of the evolution of enzymes belonging to an  ...  The advent of computational approaches to measure functional similarity between enzymes adds a new dimension to existing evolutionary studies based on sequence and structure.  ...  Authors discovered that structurally diverse superfamilies are plastic in the location of functional sites such as protein-protein binding, catalytic, ligand binding and nucleic acid binding sites.  ... 
doi:10.1016/j.sbi.2014.06.002 pmid:25000289 pmcid:PMC4139412 fatcat:jl366uxgrfchpdgknr5dl5pehm

The Natural History of Biocatalytic Mechanisms

Neetika Nath, John B. O. Mitchell, Gustavo Caetano-Anollés, Marco Punta
2014 PLoS Computational Biology  
Here we explore structure-function relationships addressing the use of chemical mechanisms by ancestral enzymes. We test the hypothesis that the oldest folds used the most mechanisms.  ...  We start by tracing biocatalytic mechanisms operating in metabolic enzymes along a phylogenetic timeline of the first appearance of homologous superfamilies of protein domain structures from CATH.  ...  structural change and the relationship between protein structure and function [6] .  ... 
doi:10.1371/journal.pcbi.1003642 pmid:24874434 pmcid:PMC4038463 fatcat:how57kfrmrhitjsskwn4l7v6bi

FunTree: a resource for exploring the functional evolution of structurally defined enzyme superfamilies

N. Furnham, I. Sillitoe, G. L. Holliday, A. L. Cuff, S. A. Rahman, R. A. Laskowski, C. A. Orengo, J. M. Thornton
2011 Nucleic Acids Research  
FunTree is a new resource that brings together sequence, structure, phylogenetic, chemical and mechanistic information for structurally defined enzyme superfamilies.  ...  Developed in tandem with the CATH database, it currently comprises 276 superfamilies covering 1800 (70%) of sequence assigned enzyme reactions.  ...  To begin to understand in detail how enzymes have evolved new functions requires the combination of protein 3D structure, sequence, phylogenetic, chemical and mechanistic data.  ... 
doi:10.1093/nar/gkr852 pmid:22006843 pmcid:PMC3245072 fatcat:lwlpp7cazvdy5ebfxequzzujnu

A global view of structure–function relationships in the tautomerase superfamily

Rebecca Davidson, Bert-Jan Baas, Eyal Akiva, Gemma L. Holliday, Benjamin J. Polacco, Jake A. LeVieux, Collin R. Pullara, Yan Jessie Zhang, Christian P. Whitman, Patricia C. Babbitt
2017 Journal of Biological Chemistry  
Our new linker-guided strategy can be used to enrich the discovery of sequence/structure/function transitions in other enzyme superfamilies.  ...  To gain new insight into TSF structure-function relationships, we performed a global analysis of similarities across the entire superfamily and computed a sequence similarity network to guide classification  ...  Mechanistically diverse enzyme superfamilies (1) (also referred to as functionally diverse superfamilies) represent about one-third of the universe of enzyme superfamilies (2) .  ... 
doi:10.1074/jbc.m117.815340 pmid:29184004 pmcid:PMC5818174 fatcat:ncda6shkpjecfar7znsgxuct4i

Diversity in protein domain superfamilies

Sayoni Das, Natalie L Dawson, Christine A Orengo
2015 Current Opinion in Genetics and Development  
(a) Correlation of structural diversity with functional diversity in CATH domain superfamilies. Each point represents a CATH superfamily.  ...  For example, sequence similarity networks based on protein families can help in providing a com-prehensive summary of sequence, structure and function relationships in a functionally diverse superfamily  ...  A review on the relationship between functional diversity and protein structure architecture. It explores why relatively few folds have the ability to support numerous functions.  ... 
doi:10.1016/j.gde.2015.09.005 pmid:26451979 pmcid:PMC4686048 fatcat:gfsrz4jvcrerrkbbzhrh3wfsj4

Mechanistic and Bioinformatic Investigation of a Conserved Active Site Helix in α-Isopropylmalate Synthase from Mycobacterium tuberculosis, a Member of the DRE-TIM Metallolyase Superfamily

Ashley K. Casey, Michael A. Hicks, Jordyn L. Johnson, Patricia C. Babbitt, Patrick A. Frantom
2014 Biochemistry  
The characterization of functionally diverse enzyme superfamilies provides the opportunity to identify evolutionarily conserved catalytic strategies, as well as amino acid substitutions responsible for  ...  the evolution of new functions or specificities.  ...  The addition of "genomic enzymology," 6 describing enzyme catalysis from the context of structurefunction relationships among homologous members of enzyme superfamilies, to the toolbox of mechanistic  ... 
doi:10.1021/bi500246z pmid:24720347 pmcid:PMC4025573 fatcat:y3onh6qnojbexnh57u7tmsjwcu

Inference of Functional Properties from Large-scale Analysis of Enzyme Superfamilies

Shoshana D. Brown, Patricia C. Babbitt
2011 Journal of Biological Chemistry  
diverse" enzyme superfamilies.  ...  Network analyses using three functionally diverse enzyme superfamilies illustrate the use of these approaches for facile updating and comparison of available structures for a large superfamily, for creation  ...  diverse" enzyme superfamilies.  ... 
doi:10.1074/jbc.r111.283408 pmid:22069325 pmcid:PMC3249087 fatcat:xffkp77sbvhkjhd4cxf6pbs2lq

Understanding Enzyme Superfamilies

Patricia C. Babbitt, John A. Gerlt
1997 Journal of Biological Chemistry  
Although they represent several distinct family folds, the enzyme functions in each superfamily are related to their respective structural scaffolds in the same way; the proteins within each superfamily  ...  Further, the diversity of function that each superfamily represents allows an economy in the number of unique protein folds required to support life and, as a result, undoubtedly has "simplified" the course  ...  Although they represent several distinct family folds, the enzyme functions in each superfamily are related to their respective structural scaffolds in the same way; the proteins within each superfamily  ... 
doi:10.1074/jbc.272.49.30591 pmid:9388188 fatcat:ynqelj76cjda7cw6m47joaoa6e
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