Hydrolysis of tetriso by an enzyme derived from Pseudomonas diminuta as a model for the detoxication of O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX).
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 Km 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, Ki = 8.7 x 10(-4) M. The DFP hydrolysis product, diisopropyl phosphate, was a competitive inhibitor, Ki = 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 P-S 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.
Hoskin
F C
FC
Marine Biological Laboratory, Woods Hole, MA 02543.
Walker
J E
JE
Dettbarn
W D
WD
Wild
J R
JR
D043303:Aryldialkylphosphatase; D002614:Chelating Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D004950:Esterases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D008658:Inactivation, Metabolic; D007531:Isoflurophate / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism*; D009946:Organothiophosphorus Compounds / Q000378:metabolism*; D011549:Pseudomonas / Q000201:enzymology*; D012999:Soman / Q000378:metabolism
D043303:Aryldialkylphosphatase; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D004950:Esterases; D007531:Isoflurophate; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D012999:Soman; C091319:Tetriso; C009680:VX-agent