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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. November 2003, Volume 2, Number 11, 712-722 |
Energetics of Catalytic Reaction of Acetylcholinesterase (AChE)
with Acetylcholine (ACh): Role of the Oxyanion Hole
Manabu Igarashi, Teruo Ishibashi, Jun Nishihira, and Hiroto Tachikawa
Internet Electron. J. Mol. Des. 2003, 2, 712-722
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Abstract:
Acetylcholinesterase (AChE) is one of the enzymes which
synthesize the neurotransmitter acetylcholine (ACh) by the
transition of acyl-groups of acetyl CoA and it is an important
enzyme in biochemistry. It is also known that AChE catalyzes
the hydrolysis with a high catalytic efficiency. However, details
of the reaction mechanism are still in controversy. In particular,
the effects of the oxyanion hole on the energetics of the catalytic
reaction are not clearly understood. In the present study, potential
energy diagrams for the catalytic reaction of AChE with ACh
have been determined by means of ab initio and hybrid-DFT
calculations using the model molecules of AChE and ACh. We
have focused our attention mainly on the role of the oxyanion
hole in the reaction. The ab initio and hybrid-DFT calculations
were carried out at the HF/3-21G(d)//HF/3-21G(d) and
B3LYP/6-311G(d,p)//HF/ 3-21G(d) levels of theory. The
pre-complex composed of AChE and ACh, expressed by
AChE-ACh, was 10.3 kcal/mol more stable than that of its separated
state (AChE + ACh). The activation barrier for the formation of
the tetrahedral intermediate from AChE-ACh was calculated to
be 20.5 kcal/mol higher in energy than the pre-complex, and the
tetrahedral intermediate is 18.0 kcal/mol higher relative to the
pre-complex. In addition, the effect of the oxyanion hole was
examined. The activation energy was decreased from 20.5 to
10.4 kcal/mol by the interaction with the oxyanion hole. The
present calculated value (10.4 kcal/mol) was in good agreement
with recent experimental one (12.0 kcal/mol). The mechanism of
the formation of the tetrahedral intermediate from AChE-ACh
was discussed on the basis of theoretical results.
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