HYDROLYSIS OF TETRISO BY AN ENZYME DERIVED FROM PSEUDOMONAS-DIMINUTA AS A MODEL FOR THE DETOXICATION OF O-ETHYL S-(2-DIISOPROPYLAMINOETHYL) METHYLPHOSPHONOTHIOLATE(VX)

被引:45
作者
HOSKIN, FCG
WALKER, JE
DETTBARN, WD
WILD, JR
机构
[1] USA,NATICK RES DEV & ENGN CTR,NATICK,MA 01760
[2] VANDERBILT UNIV,SCH MED,DEPT PHARMACOL,NASHVILLE,TN 37212
[3] TEXAS A&M UNIV,DEPT BIOCHEM & BIOPHYS,COLLEGE STN,TX 77843
关键词
ACETYLCHOLINESTERASE; DETOXICATION; ORGANOPHOSPHORUS HYDROLASE (OPH); PSEUDOMONAS DIMINUTA; TETRISO; VX;
D O I
10.1016/0006-2952(94)00496-9
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
An enzyme termed organophosphorus hydrolase (OPH), derived from Pseudomonas diminuta, had been found previously to hydrolyze the powerful acetylcholinesterase (AChE) inhibitor O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX). This enzyme has now been shown to be correlated with the loss of AChE inhibitory potency (detoxication). OPH also hydrolyzed and detoxified the VX analogue, O,O-diisopropyl S-(2-diisopropylaminoethyl) phosphorothiolate (Tetriso), also a potent AChE inhibitor, about five times faster than VX. The K-m for the hydrolysis of the P-S bond of Tetriso was 6.7 x 10-(3) M. OPH also hydrolyzed diisopropylphosphorofluoridate (DFP) 50-60 times faster than Tetriso, and 1,2,2-trimethylpropyl methylphosphonofluoridate (Soman) about seven times faster than Tetriso. DFP was a non-competitive inhibitor of Tetriso hydrolysis, K-i = 8.7 x 10(-4) M. The DFP hydrolysis product, diisopropyl phosphate, was a competitive inhibitor, K-i = 2.3 x 10(-4) M. The rate of detoxication of Tetriso compared with the rate of hydrolysis suggests that OPH may not be totally specific for PS bond cleavage. OPH was inhibited completely by 1.5 x 10(-4) M 8-hydroxyquinoline-5-sulfonate or 1,10-phenanthroline, both transition element chelators, but inhibited only partially by EDTA, a much more potent chelator.
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页码:711 / 715
页数:5
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