Isofluorophate reaction at AChE esteratic site, aging, spontaneous reactivation, and oxime reactivation. Left, the nucleophilic attack on the phosphorus of isofluorophate by the serine oxygen. This results in a stable phosphorylated enzyme intermediate, which undergoes dephosphorylation at a negligible rate (top). A more favorable reaction is the loss of an isopropoxy group, a process termed aging (bottom). This renders the phosphorylated enzyme resistant to dephosphorylation by an oxime. The original phosphorylated intermediate (center) will react with the nucleophilic oxygen of pralidoxime (2-PAM), resulting in dephosphorylation of the enzyme and formation of an oxime phosphonate (lower right).
Although the spontaneous hydrolysis of a phospho-rylated enzyme is generally very slow, compounds called oximes can cause dephosphorylation (Fig. 12.4). Pralidoxime chloride (2-PAM) (Protopam chloride) is an oxime used therapeutically to reactivate phosphory-lated AChE. It has the additional feature that its quaternary ammonium group binds to the anionic site of the enzyme and thereby promotes dephosphorylation. If the oxime is not administered soon enough (minutes to hours) after AChE has been inhibited, an alkoxy group may be lost from the phosphorylated enzyme. This reaction is called aging. Once aging has occurred, oximes can no longer regenerate free enzymes. The rate of aging appears to depend both on the nature of the enzyme (AChE or pseudo-ChE) and on the particular inhibitor employed. Since pralidoxime is a quaternary amine, it does not cross the blood-brain barrier, and it is not useful for reactivating cholinesterases in the CNS.
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