ON THE POSSIBLE REACTION PATHWAY FOR THE ACYLATION OF ACHE-CATALYZED HYDROLYSIS OF ACH - SEMIEMPIRICAL QUANTUM-CHEMICAL STUDY

The acylation process in the acetylcholinesterase (AChE)-catalyzed hyd rolysis of the neurotransmitter, acetylcholine (ACh), has been determi ned with the semiempirical quantum chemical calculation method AM1 usi ng the model molecules extracted from the X-ray crystal structure of T orpedo Californica AChE. For the sake of identifying the microfeatures of the mechanism of this reaction, two types of possible mechanisms, stepwise mechanism and cooperative mechanisms, were proposed and studi ed with AM1 methods. All the model molecules for the possible reactant s, intermediates, transition states, and products in the reaction path ways of the two mechanisms were obtained. Energy profiles, the structu ral properties of the transition states, indicate that the acylation o f AChE-catalyzed hydrolysis of ACh adopts the cooperative mechanism, i .e., the proton transfer from Ser220 of AChE to His440 occurs simultan eously with the nucleophilic attack of Ser200 to the carbonyl carbon a tom of ACh. This result is in agreement with the kinetic data and the secondary isotope effects of AChE-catalyzed reactions. (C) 1998 John W iley & Sons, Inc.