The carbamates and organophosphates covalently modify the active site serine, as illustrated in the lower portion of scheme 5-10, to form either a carbamylated enzyme or an enzyme phosphotriester, both of which undergo hydrolysis so slowly as to effectively inactivate the enzyme. The upper portion of scheme 5-10 represents the enzymatic hydrolysis of acetylcholine, in which ROH is choline: (CH3)3N+CH2CH2OH.
The covalently modified acetylcholinesterase can be reactivated by the addition of nucleophiles that react more rapidly with the phosphotriester or carbamyl groups than water in the imperceptively slow enzymatic hydrolysis. Pyridine aldoximine methiodide (PAM) is an effective antidote for poisoning by organophosphate compounds, because it combines an oxime nucleophile with the pyridinium cation that helps to target the drug to the active site much like the cationic inhibitors (Frode and Wilson, 1971).
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