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Chem Biol. 2012 Apr 20;19(4):456-66. doi: 10.1016/j.chembiol.2012.01.017.

Evolved stereoselective hydrolases for broad-spectrum G-type nerve agent detoxification.

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  • 1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.

Abstract

A preferred strategy for preventing nerve agents intoxication is catalytic scavenging by enzymes that hydrolyze them before they reach their targets. Using directed evolution, we simultaneously enhanced the activity of a previously described serum paraoxonase 1 (PON1) variant for hydrolysis of the toxic S(P) isomers of the most threatening G-type nerve agents. The evolved variants show ≤340-fold increased rates and catalytic efficiencies of 0.2-5 × 10(7) M(-1) min(-1). Our selection for prevention of acetylcholinesterase inhibition also resulted in the complete reversion of PON1's stereospecificity, from an enantiomeric ratio (E) < 6.3 × 10(-4) in favor of the R(P) isomer of a cyclosarin analog in wild-type PON1, to E > 2,500 for the S(P) isomer in an evolved variant. Given their ability to hydrolyze G-agents, these evolved variants may serve as broad-range G-agent prophylactics.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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PMID:
22520752
[PubMed - indexed for MEDLINE]
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