| Project/Area Number |
06680644
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biophysics
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| Research Institution | CHIBA UNIVERSITY |
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Principal Investigator |
TSUDA Minoru (1995) CHIBA UNIVERSITY,FACULTY OF PHARMACEUTICAL SCIENCES,PROFESSOR, 薬学部, 教授 (90009506)
笈川 節子 (1994) 千葉大学, 薬学部, 助教授 (60101359)
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| Co-Investigator(Kenkyū-buntansha) |
HATA Masayuki CHIBA UNIVERSITY,FACULTY OF PHARMACEUTICAL SCIENCES,RESEARCH ASSOCIATE, 薬学部, 助手 (50241972)
OIKAWA Setsuko CHIBA UNIVERSITY,FACULTY OF PHARMACEUTICAL SCIENCES,ASSOCIATE PROFESSOR, 薬学部, 助教授 (60101359)
津田 穣 千葉大学, 薬学部, 教授 (90009506)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1995: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1994: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | Acetylcholine / Choline Esterase / Serine Protease / Hydrolysis / Proton-relay Mechanism / Molecular Orbital Calculation / Molecular Dynamics / Catalytic Triad / 分子動力学計算 / 量子化学計算 / 局所密度汎関数法 / アニオニックサイト / 抗痴呆薬 / 加水分解反応機構 / セリンオキソニウムイオン / 活性中心 |
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| Research Abstract |
Acetylcholine esterase is one of serine-protease, whic singularly acts on acetylcholine, a neuro-chemical transmitter, to hydrolyze into choline and acetic acid at cholinargetic synapses. The inhibitor can remain acetylcholine and stimulate cholinargetic action strong. Recently the inhibitor is noted to be a novel medicine, an anti-dementia agent, which improves Alzheimer symptoms induced from deficiency of acetylcholine in cerebral cortex. Aiming at development of new anti-dementia, we investigate the enzymatic reaction mechanism of acetylcholine esterase at the atomic level by means of quantum chemistry and molecular dynamics. The results obtained are as follows : (1) Glu 199 is the only one residue that can act as the "anionic site", which can hold a quaternary ammonium cation of acetylcholine at the appropriate position during the hydrolysis. This situation is reasonable for such an extremely high rate of acetylcholine esterase. (2) Theoretical calculations on a reaction model for the active site constructed from the "catalytic triad" (Ser 200-His 40-Glu 327), acetylcholine, Glu 199 as the anionic site, and two glycines as the "oxyanion hole", reveal that the protonrelay mechanism suggested by Blow in 1969 is valid effectively, where the rate-determining step generating the Ser-O anion at the active center is divided into two steps and the activation energy is reduced by 10 kcal/mol lower. This is a significant support for the proton-relay mechanism which has been a point of discussion on the serine-protease enzymatic action. (3) We summarized our research and proposed a guiding principle for the drug-design of the inhibitor.
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