Acetylcholinesterase slow reactivation

Organophosphorus esters are known to react with a serine hydroxyl group in the active site of the acetylcholinesterase protein (Ecobichon 1991 Murphy 1986). Some organophosphorus esters (e.g., diisopropyl fluorophosphate, [DFP]) bind irreversibly, while others bind in a slowly reversible fashion, thereby leading to a slow reactivation (dephosphorylation) of the enzyme. A process known as "aging" has also been described in which reversibly bound compounds are changed with time to moieties that are essentially irreversibly... 

Figure 7.49 General scheme for acetylcholinesterase action. R may be equal to C or P. If R=P, then (R3) is present. The group OR, may be replaced by SR, giving R,SH on hydrolysis (reaction 1). IF R=P, reaction 2 is very slow, giving inactivated enzyme. The rate of hydrolysis or reactivation depends on the nature of R2 and R3.

Tabun-inhibited enzyme (an O-ethyl N,N-dimethylamidophosphoro derivative) is slow to reactivate and Heilbronn (1963) found no detectable spontaneous reactivation with human acetylcholinesterase. The reasons for this are becoming more clear. Tabun binding of mouse acetylcholinesterase causes conformational changes in the enzyme that may stabilize the enzyme-inhibitor complex even without ageing of the complex (Ekstrom et al., 2006). 

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