Organophosphate Inhibitors of ACh E 4 n Enzyme

Organophosphate Inhibitors of ACh. E (4) n Enzyme inhibition by these agents can be reversed by cholinesterase reactivators such as pralidoxime if administered before “aging” of ACh. E has occurred. Inhibition by agents that undergo rapid “aging” is not reversed. n Except for echothiophate, these agents are extremely lipid soluble, and some are very volatile.

Diisopropylflurophosphate (DFP) is a Substrate for ACh. E

The Extremely Slow Hydrolysis of Phosphorylated-ACh. E New enzyme synthesis is required for recovery of enzyme function

Various “States” of Acetylcholinesterase Clockwise: free ACh. E, acetylated ACh. E, carbamylated ACh. E, phosphorylated ACh. E

Acetylated-ACh. E Is Very Rapdily Hydrolyzed ACh. E + Acetylcholine ACh. E-acetylated + choline ACh. E-acetylated + H 2 O ACh. E + acetate Hydrolysis of ACh. E-acetylated is rapid, in the order of microseconds P

Carbamylated-ACh. E Is Hydrolyzed Slowly ACh. E + Carbamyl inhibitor ACh. E-carbamylated + noncarbamylated metabolite ACh. E-carbamylated + H 2 O ACh. E + carbamic acid derivative Hydrolysis of the ACh. E-carbamylated is slow, in the order of hours. The carbamylated enzyme is reversibly inhibited, and recovery of function is in the order of hours Enzyme after phosphorylation by neostigmine

Phosphorlylated-ACh. E Is Hydrolyzed Extremely Slowly ACh. E + organophosphate inhibitor ACh. E-phosphorylated + nonphosphorylated metabolite ACh. E-phosphorylated + H 2 O ACh. E + phosphorylated derivative Hydrolysis of the ACh. E-phosphorylated is extremely slow, in the order of days. The phosphorylated enzyme is considered to be irreversibly inhibited, and recovery of function is in the order of days. Pralidoxime, a reactivating agent, may be adminstered to a subject before the enzyme has “aged. ” Enzyme after phosphorylation by DFP