title: Stereoselective inactivation of Torpedo californica acetylcholinesterase by isomalathion: inhibitory reactions with (1R)- and (1S)-isomers proceed by different mechanisms.
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.
authors.affiliation: Toxicology Program, Department of Environmental Health Sciences, The University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Doorn
authors.forename: Charles M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Robert B
authors.initials: RB
authors.lastname: Christner
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Richardson
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000302:isolation & purification; D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D008294:Malathion / Q000737:chemistry*; D013058:Mass Spectrometry / Q000379:methods; D008958:Models, Molecular; D013237:Stereoisomerism; D014101:Torpedo
chemical_list: D002800:Cholinesterase Inhibitors; C018326:isomalathion; D000110:Acetylcholinesterase; D008294:Malathion