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Theoretical studies on the possible reaction pathway for the deacylation of the AChE‐catalyzed reaction
Author(s) -
Wang Qin Mi,
Jiang Hua Liang,
Chen Kai Xian,
Ji Ru Yun,
Ye YuanJie
Publication year - 1999
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/(sici)1097-461x(1999)74:3<315::aid-qua4>3.0.co;2-y
Subject(s) - chemistry , acylation , nucleophile , catalysis , transition state , acetylcholinesterase , molecule , kinetic isotope effect , reaction mechanism , leaving group , concerted reaction , computational chemistry , activation energy , hydrolysis , organic chemistry , enzyme , physics , deuterium , quantum mechanics
Acetylcholinesterase (AChE)‐catalyzed hydrolysis of the neurotransmitter, acetylcholine (ACh), occurs via an acylation and deacylation process. The deacylation process was studied theoretically by the semiempirical quantum chemical method AM1 using the model molecules. To investigate the micro features of the deacylation process, two types of possible reaction mechanisms, the stepwise mechanism and the cooperative mechanism, were proposed and studied. All optimized structures of the model molecules for the possible reactants, intermediates, transition states, and products in the reaction pathway of the two possible mechanisms were obtained. Energy profiles and the structural properties of the transition states indicated that the deacylation process proceeds through the cooperative mechanism, that is, the proton transfer from H 2 O to His440 occurs simultaneously with the nucleophilic attack of the oxygen atom of the H 2 O to the carbonyl carbon of the acylenzyme. Considering the reaction mechanism of acylation, the first process in AChE‐catalyzed hydrolysis of ACh, studied in our previous article, we can conclude that both the acylation and deacylation process limit the rate of the entire AChE‐catalyzed reaction. Four transition states exist in the whole pathway of the AChE‐catalyzed reaction. The rehybridization of the transition state was found. These results are in agreement with the kinetics data and the secondary isotope effects of AChE‐catalyzed reactions. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 74: 315–325, 1999