| Project/Area Number |
18K05072
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 33010:Structural organic chemistry and physical organic chemistry-related
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| Research Institution | Ibaraki University |
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Principal Investigator |
Mori Seiji 茨城大学, 理工学研究科(理学野), 教授 (50332549)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 量子化学計算 / QM/MM法 / 分子動力学シミュレーション / 反応機構 / 酵素 / 非共有結合性相互作用 / 非共有結合相互作用 / QM/MM計算 / 天然有機化合物 / ビリン還元酵素 / 分子動力学計算 / プロトン化状態 / プロスタグランジン合成酵素 / 酵素反応機構 |
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| Outline of Final Research Achievements |
In this research project, we employed computational chemistry methods to investigate regio- and stereo-selective enzymatic reaction mechanisms. 3α-Hydroxysteroid dehydrogenase (3α-HSD) is an enzyme, that is essential in the regulation of the concentration of 5α-dihydrotestosterone (5α-DHT) in the prostate. It catalyzes the hydride reduction of 5α-DHT to 3α-androstanediol, which activates androgen receptors. Molecular dynamic (MD) simulations and hybrid ONIOM-type quantum mechanics/molecular mechanics (QM/MM) calculations were performed, and a new important aspect of the non-covalent interactions between a cofactor NADPH, water molecules, and the enzyme were found in this study. This work is accepted in a scientific journal. In addition, the absolute stereochemistry configurations of several triterpenes (biological active natural products) were determined.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で明らかになった反応機構や、酵素のアミノ酸残基と補因子の間に働く非共有結合性相互作用によって、酵素反応にかかわる酵素自身のアミノ酸残基を変異させ制御することによるタンパク質エンジニアリングや、酵素のモデル化合物を用いることによる人工酵素の設計、遷移状態アナログに基づく薬剤の開発にも役立つことが期待される。
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