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National Institute of Environmental Health Sciences

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Publication Detail

Title: Stereoselective inactivation of Torpedo californica acetylcholinesterase by isomalathion: inhibitory reactions with (1R)- and (1S)-isomers proceed by different mechanisms.

Authors: Doorn, Jonathan A; Thompson, Charles M; Christner, Robert B; Richardson, Rudy J

Published In Chem Res Toxicol, (2003 Aug)

Abstract: The present study was undertaken to test the hypothesis that acetylcholinesterase (AChE) inhibition by isomalathion stereoisomers proceeds with different primary leaving groups for (1R)- and (1S)-isomers. Consistent with results obtained with enzyme from other species, AChE from Torpedo californica (TcAChE) was stereoselectively inhibited by isomalathion isomers with the (1R,3R)-isomer exhibiting greater potency than (1S,3S)-isomalathion. TcAChE modified by (1R)-isomers readily reactivated in the presence of 2-pralidoxime methiodide (2-PAM), whereas enzyme inhibited by (1S)-isomalathions was intractable toward reactivation. Computer-based molecular modeling showed that the ligand positioned as the primary leaving group was diethyl thiosuccinyl for (1R)-isomers and thiomethyl for (1S)-isomalathions. Mass spectral analysis revealed that inhibition of TcAChE by (1R)-isomers resulted in an O,S-dimethyl phosphate adduct, as expected from expulsion of the diethyl thiosuccinyl ligand. In contrast, inactivation of the enzyme by (1S)-isomalathions yielded an O-methyl phosphate adduct, consistent with initial loss of thiomethyl followed by displacement of the diethyl thiosuccinyl group. The findings demonstrate that the inhibitory reactions of TcAChE with (1R)- and (1S)-isomalathions proceed by different mechanisms involving distinct primary leaving groups.

PubMed ID: 12924923 Exiting the NIEHS site

MeSH Terms: Acetylcholinesterase/chemistry*; Acetylcholinesterase/isolation & purification; Animals; Binding Sites; Cholinesterase Inhibitors/pharmacology*; Comparative Study; Malathion/chemistry*; Models, Molecular; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.; Spectrum Analysis, Mass/methods; Stereoisomerism; Torpedo*

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