INTERACTION OF ACETYLCHOLINESTERASE WITH THE ENANTIOMERS OF MALAOXON AND ISOMALATHION

The bimolecular reaction constants (k(i)), dissociation constants (K(d )), and phosphorylation constants (k(p)) were determined for the enant iomers of malaoxon against rat brain acetylcholinesterase, and for the stereoisomers of isomalathion against rat brain acetylcholinesterase and electric eel acetylcholinesterase. (R)-Malaoxon was an 8.6-fold mo re potent anti-cholinesterase than (S)-malaoxon. Isomalathion stereois omers with the R configuration at carbon were 3-13-fold stronger inhib itors than those with the S configuration. The isomalathion stereoisom ers with the R configuration at phosphorus were 4.3-8.8-fold stronger inhibitors of rat brain acetylcholinesterase, yet 3.4-5.8-fold weaker inhibitors of electric eel acetylcholinesterase, than the isomalathion stereoisomers with the S configuration at phosphorus. The rat brain a cetylcholinesterase spontaneous (k0 = approximately 13.0 X 10(-3) min- 1) and oxime-mediated (k(oxime) = 51.0 x 10(-3) min-1) reactivation ra te constants following inhibition by isomalathion stereoisomers with t he R configuration at phosphorus were comparable to spontaneous (11.3 x 10(-3) min-1) and oxime-mediated (50.2 x 10(-3) min-1) reactivation rates obtained for (S)-isoparathion methyl. These data support a commo n phosphorylation mechanism, namely, the displacement of the thiosucci nyl moiety from isomalathion stereoisomers with the R configuration at phosphorus, and displacement of the p-nitrophenoxy ligand from (S)-is oparathion methyl to form the same O,S-dimethyl phosphorothiolated enz yme. Rat brain acetylcholinesterase inhibited by the isomalathion ster eoisomers with the S configuration at phosphorus were refractory to re activation, suggesting an alternate mechanism of inhibition, i.e., the loss of the methylthio ligand. Several mechanisms are proposed to acc ount for the subsequent nonreactivation. Similar reactivation kinetics are predicted for electric eel acetylcholinesterase inhibited by the isomalathion stereoisomers on the basis of k(p) values.