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Reaction Of Acetylcholinesterase With Organophosphonates

H. Berman
Published 1995 · Chemistry

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Irreversible inhibition of acetylcholinesterase (AchE) by organophosphorus agents is rapid, proceeding at rates that, in general, exceed 105–106 M−1-min−1. Numerous instances occur in which the reaction velocity, proceeding at rates greater than 108 M−1-min−1, approaches within an order of magnitude of the diffusion limitation (Berman and Leonard, 1989). The rapidity of organophosphorus reactions with AchE is striking, especially so since these molecules, having tetrahedral symmetry, occupy a measurable volume, and they engender a more complex array of steric interactions than, for example, the planar, symmetrical substrate acetylcholine. Such reactivity of organophosphonates is even more remarkable since the catalytically reactive residues exist at the base of a deep gorge, 20 A in depth, that is deeper than it is wide, is tightly circumscribed, and offers ample opportunity for unfavorable steric interactions. Indeed, there exists within the gorge, about half-way between the enzyme surface and the base, a pronounced ledge — or restriction — that, as seen in the crystal state, would seem to restrict free diffusion of a large ligand in or out of the gorge (Sussman, et al., 1991). As such, information derived from the crystal structure provides no easy explanations for the rapid covalent reactivity of AchE toward a wide variety of organophosphorus agents. Systematic study of a defined family of structurally-related organophosphonates can provide some clues as to interactions of importance in the docking and reactivity of large molecules within the active center.



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