Document Detail

Catalytic versatility and backupsin enzyme active sites: The case of serum paraoxonase 1.
MedLine Citation:
PMID:  22387469     Owner:  NLM     Status:  Publisher    
The origins of enzyme specificity are well established. However, the molecular details underlying the ability of a single active site to promiscuously bind different substrates and catalyze different reactions remainlargely unknown. To better understanding the molecular basis of enzyme promiscuity, we studied the mammalian serum paraoxonase-1 (PON1) whose native substrates are lipophilic lactones. We describe the crystal structures of PON1 at a catalytically relevant pH and of its complex with a lactone analogue. The various PON1 structures, and the analysis ofactive-site mutants, guided the generation ofdocking models of the various substrates and their reaction intermediates. The modelssuggestthat promiscuity is driven by coincidental overlaps between the reactive intermediate for the native lactonase reaction and the ground and/or intermediate statesofthe promiscuous reactions. This overlap is also enabled by different active site conformations: the lactonase activity utilizes one active-site conformationwhereasthe promiscuous phosphotriesterase activity utilizes another. The hydrolysis of phosphotriesters, and of the aromatic lactonedihydrocoumarin, is also driven by an alternative catalytic mode that uses only a subset of the active-site residues utilized for lactone hydrolysis. Indeed, PON1's active site shows a remarkable level ofnetworking and versatilitywherebymultiple residues share the same task, and individual active-site residues perform multiple tasks (e.g. binding the catalytic calcium and activating the hydrolytic water).Overall, the coexistence of multiple conformationsand of alternative catalytic modes within the same active siteunderline PON1's promiscuity and evolutionary potential.
Moshe Ben-David; Mikael Elias; Jean-Jacques Filippi; Elisabet Duñach; Israel Silman; Joel L Sussman; Dan S Tawfik
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-1
Journal Detail:
Title:  Journal of molecular biology     Volume:  -     ISSN:  1089-8638     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Ltd.
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
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