Doorn_2003_Chem.Res.Toxicol_16_958

Reference

Title : Stereoselective inactivation of Torpedo californica acetylcholinesterase by isomalathion: inhibitory reactions with (1R)- and (1S)-isomers proceed by different mechanisms - Doorn_2003_Chem.Res.Toxicol_16_958
Author(s) : Doorn JA , Thompson CM , Christner RB , Richardson RJ
Ref : Chemical Research in Toxicology , 16 :958 , 2003
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.

PubMedSearch : Doorn_2003_Chem.Res.Toxicol_16_958
PubMedID: 12924923

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Citations formats

Doorn JA, Thompson CM, Christner RB, Richardson RJ (2003)
Stereoselective inactivation of Torpedo californica acetylcholinesterase by isomalathion: inhibitory reactions with (1R)- and (1S)-isomers proceed by different mechanisms
Chemical Research in Toxicology 16 :958

Doorn JA, Thompson CM, Christner RB, Richardson RJ (2003)
Chemical Research in Toxicology 16 :958