Theoretical studies on the possible reaction pathway for the deacylation of the AChE-catalyzed reaction

Acetylcholinesterase (AChE)-catalyzed hydrolysis of the neurotransmitter, a cetylcholine (ACh), occurs via an acylation and deacylation process. The de acylation process was studied theoretically by the semiempirical quantum ch emical method AM1 using the model molecules. To investigate the micro featu res of the deacylation process, two types of possible reaction mechanisms, the stepwise mechanism and the cooperative mechanism, were proposed and stu died. All optimized structures of the model molecules for the possible reac tants, intermediates, transition states, and products in the reaction pathw ay of the two possible mechanisms were obtained. Energy profiles and the st ructural properties of the transition states indicated that the deacylation process proceeds through the cooperative mechanism, that is, the proton tr ansfer from H2O to His440 occurs simultaneously with the nucleophilic attac k of the oxygen atom of the H2O to the carbonyl carbon of the acylenzyme. C onsidering the reaction mechanism of acylation, the first process in AChE-c atalyzed hydrolysis of ACh, studied in our previous article, we can conclud e that both the acylation and deacylation process limit the rate of the ent ire AChE-catalyzed reaction. Four transition states exist in the whole path way of the AChE-catalyzed reaction. The rehybridization of the transition s tate was found. These results are in agreement with the kinetics data and t he secondary isotope effects of AChE-catalyzed reactions. (C) 1999 John Wil ey & Sons, Inc.