Document Detail


Stereoselective hydrolysis of pyrethroid-like fluorescent substrates by human and other mammalian liver carboxylesterases.
MedLine Citation:
PMID:  16167828     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mammalian hepatic carboxylesterases (CEs) play important roles in the detoxification of ester-containing pyrethroids, which are widely used for the control of agricultural pests and disease vectors such as mosquitoes. Pyrethroids and pyrethroid-like fluorescent substrates exhibit a consistent pattern of stereoselective hydrolysis by a recombinant murine hepatic CE. We sought to understand whether this pattern is maintained in other hepatic CEs and to unravel the origin of the stereoselectivity. We found that all hepatic CEs tested displayed a consistent pattern of stereoselective hydrolysis: the chiral center(s) in the acid moiety more strongly influenced stereoselective hydrolysis than the chiral center in the alcohol moiety. For cypermethrin analogues with a cyclopropane ring in the acid moiety, trans-isomers were generally hydrolyzed faster than the corresponding cis-isomers. For fenvalerate analogues without a cyclopropane ring in the acid moiety, 2R-isomers were better substrates than 2S-isomers. These general hydrolytic patterns were examined by modeling the pyrethroid-like analogues within the active site of the crystal structure of human carboxylesterase 1 (hCE1). Stereoselective steric clashes were found to occur between the acid moieties and either the catalytic Ser loop (residues 219-225) or the oxyanion hole (residues140-144). These clashes appeared to explain the stereopreference between trans- and cis-isomers of cypermethrin analogues, and the 2R- and 2S-isomers of fenvalerate analogues by hCE1. The implications these findings have on the design and use of effective pesticides are discussed.
Authors:
Huazhang Huang; Christopher D Fleming; Kosuke Nishi; Matthew R Redinbo; Bruce D Hammock
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  18     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2005 Sep 
Date Detail:
Created Date:  2005-09-19     Completed Date:  2005-12-23     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1371-7     Citation Subset:  IM    
Affiliation:
Department of Entomology and Cancer Research Center, University of California, Davis, California 95616, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carboxylic Ester Hydrolases / chemistry,  metabolism*
Humans
Hydrolysis
Kinetics
Liver / enzymology*
Mice
Molecular Structure
Nitriles / chemistry,  metabolism
Pyrethrins / chemistry*,  metabolism*
Rats
Spectrometry, Fluorescence
Stereoisomerism
Substrate Specificity
Grant Support
ID/Acronym/Agency:
AI58267/AI/NIAID NIH HHS; CA98468/CA/NCI NIH HHS; P30 ES 05707/ES/NIEHS NIH HHS; P30 ES005707-119017/ES/NIEHS NIH HHS; P42 ES004699-19/ES/NIEHS NIH HHS; P42 ES04699/ES/NIEHS NIH HHS; R37 ES002710-25/ES/NIEHS NIH HHS; R37 ES02710/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Nitriles; 0/Pyrethrins; 1TR49121NP/cypermethrin; EC 3.1.1.-/Carboxylic Ester Hydrolases; Z6MXZ39302/fenvalerate
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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