The presence of a precisely aligned active-site triad (Ser-His-Asp/Glu) in the three-dimensional structures of widely different hydrolytic enzymes has generated intense interest in the chemical modus operandi of this catalytic motif. 1 One hypothesis, which has not received wide acceptance, proposes that the imidazole of the catalytic His is mobile during enzyme function. 2 We solved the structures of the phosphonylation and dealkylation ("aging") reaction products of acetylcholinesterase (AChE; EC 3.1.1.7) and an organophosphorus (OP) inhibitor, O-ethyl-S-[2-[bis(1-meth-ylethyl) amino]ethyl] methylphosphonothioate (VX) by X-ray crystallography. The structures clearly demonstrate reversible movement of the catalytic His. Moreover, the conformational change apparently involves a hydrogen (H-) bond with a glutamate (E199) which had been implicated previously in OP and substrate reactions.
Millard CB, Koellner G, Ordentlich A, Shafferman A, Silman I, Sussman JL (1999) Reaction Products of Acetylcholinesterase and Vx Reveal a Mobile Histidine in the Catalytic Triad Journal of the American Chemical Society121: 9883-9884
Millard CB, Koellner G, Ordentlich A, Shafferman A, Silman I, Sussman JL (1999) Journal of the American Chemical Society121: 9883-9884