Reactivity and stereospecificity of neuropathy target esterase and alpha-chymotrypsin with 2-substituted-4H-1,3,2-benzodioxaphosphorin 2-oxides.
2-Substituted-4H-1,3,2-benzodioxaphosphorin 2-oxides (2-substituted-BDPOs) are of special interest as neuropathy target esterase (NTE) inhibitors because they include not only the neuropathic metabolite of tri-o-cresyl phosphate (the 2-methylphenoxy analog) but also the most potent NTE inhibitors known. These compounds react much faster with NTE than 2 standard inhibitors, O,O-diisopropyl fluorophosphonate (DFP) and mipafox. alpha-Chymotrypsin is similar to NTE in undergoing rapid inhibition by BDPOs which is known to involve phosphorylation followed by aging. NTE and alpha-chymotrypsin were compared for reaction rates with BDPOs varying in the 2-substituent as follows: 4-methyl-, 4-propyl-, and 4-hexylphenoxy; butyl, octyl and dodecyl; (S)- and (R)-butyl. The active site of NTE differs from that of alpha-chymotrypsin in preference for long-chain substituents and in stereospecificity.
Yoshida
M
M
Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112.
Wu
S Y
SY
Casida
J E
JE
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002645:Chickens; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D007531:Isoflurophate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D009422:Nervous System Diseases / Q000139:chemically induced / Q000201:enzymology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D013237:Stereoisomerism; D013997:Time Factors; D018675:Toxicity Tests
D009943:Organophosphorus Compounds; D007531:Isoflurophate; C005238:mipafox; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D002918:Chymotrypsin