It is known that the inhibition of acetylcholinesterase by isomalathion can proceed either with diethyl succinate as the leaving group or thiomethyl, depending on the specific stereoisomer of isomalathion. Does the mechanism of inhibition of AChE by the Parathion isomer O,S-Diethyl O-4-Nitrophenyl thiophosphate (Or its dimethyl analog) likewise depend on the chirality of the molecule, or is 4-nitrophenyl the leaving group for both stereoisomers?

Reference: Doorn, J. A., Thompson, C. M., Christner, R. B., & Richardson, R. J. (2003). Stereoselective Inactivation ofTorpedo californicaAcetylcholinesterase by Isomalathion: Inhibitory Reactions with (1R)- and (1S)-Isomers Proceed by Different Mechanisms. Chemical Research in Toxicology, 16(8), 958–965. doi:10.1021/tx030026e


1 Answer 1


It would appear that the mechanism of inhibition of AChE by both stereoisomers of isoparathion (Or, at least, its methyl analog) proceeds through the expulsion of the 4-nitrophenoxy leaving group. Several papers have studied the inhibition kinetics of isomalathion and compared the results to those of isoparathion. All of them seem to agree that, at least for isoparathion methyl, AChE inhibition proceeds through the expulsion of the same leaving group, but the O,S-dimethyl phosphorylated AChE would be chiral, as is expected. Furthermore, the inhibition, reactivation, and aging reaction rate constants would also differ depending on the stereoisomer of isoparathion.


Berkman, C. E., Quinn, D. A., & Thompson, C. M. (1993). Interaction of acetylcholinesterase with the enantiomers of malaoxon and isomalathion. Chemical Research in Toxicology, 6(5), 724–730. doi:10.1021/tx00035a019


Jianmongkol, S., Marable, B. R., Berkman, C. E., Talley, T. T., Thompson, C. M., & Richardson, R. J. (1999). Kinetic Evidence for Different Mechanisms of Acetylcholinesterase Inhibition by (1R)- and (1S)-Stereoisomers of Isomalathion. Toxicology and Applied Pharmacology, 155(1), 43–53. doi:10.1006/taap.1998.8608


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