Synthesis and 31P chemical shift identification of tripeptide active site models that represent human serum acetylcholinesterase covalently modified at serine by certain organophosphates

Chemical Research in Toxicology
C M ThompsonO P Rodriguez

Abstract

Most organophosphorus (OP) insecticides impart their toxic action via inhibition of cholinesterases by reacting at an essential serine hydroxyl group. The inhibition process is dependent upon the reactivity, stereochemistry, leaving group, and the mechanism of phosphorylation and/or reactivation (or aging) inherent to the OP compound under consideration. Because a wide array of phosphorylated structures are possible following inhibition by an OP, a simple model system was sought to investigate the mechanistic details of these and related reactions. In the present study, the tripeptide N-CBZ-Glu-Ser(OH)-Ala-OEt (chosen as a truncated form of human serum cholinesterase) was chemically modified at the serine hydroxyl group by various O-methyl phosphate groups and the 31P NMR chemical shift recorded. Six tripeptides, representing (a) phosphorylation by dimethyl phosphorothionates (N-CBZ-Glu-Ser[O-P(S)(OMe)2]Ala-OEt; 5), (b) phosphorylation by dimethyl phosphates (N-CBZ-Glu-Ser[O-P(O)(OMe)2] Ala-Oet; 6), (c) phosphorylation by O,S-dimethyl phosphorothiolates (N-CBZ-Glu-Ser[O-P(O)(OMe)(SMe)]Ala-OEt; 7), (d) aging following inhibition by dimethyl phosphorothionates (N-CBZ-Glu-Ser[O-P(O)(OMe)(S-)]Ala-OEt; 8), (e) aging following inhibi...Continue Reading

References

Aug 1, 1959·Biochimica Et Biophysica Acta·F BERENDSF A DEIERKAUF

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Citations

Mar 31, 2006·Journal of Enzyme Inhibition and Medicinal Chemistry·Khodayar GholivandHossein Naderimanesh
Apr 1, 2010·Journal of Enzyme Inhibition and Medicinal Chemistry·Khodayar GholivandZahra Shariatinia
Dec 30, 2006·Journal of Enzyme Inhibition and Medicinal Chemistry·Khodayar GholivandKhosro Khajeh
Jan 15, 2005·Journal of Enzyme Inhibition and Medicinal Chemistry·Khodayar GholivandHossein Naderi-Manesh

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