Effects of multiple binding sites of CYP2C9 on its allosteric modulation
| Project/Area Number |
18K06613
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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 47020:Pharmaceutical analytical chemistry and physicochemistry-related
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| Research Institution | Doshisha Women's College of Liberal Arts |
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Principal Investigator |
Maekawa Keiko 同志社女子大学, 薬学部, 教授 (70270626)
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| Co-Investigator(Kenkyū-buntansha) |
安達 基泰 国立研究開発法人量子科学技術研究開発機構, 量子生命科学領域, 上席研究員(定常) (60293958)
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| Project Period (FY) |
2018-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 薬物代謝酵素 / 遺伝子多型 / X線結晶構造解析 / チトクロームP450 / 構造活性相関 / CYP2C9 |
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| Outline of Final Research Achievements |
CYP2C9, a drug-metabolizing enzyme, is an allosteric enzyme with multiple substrate-binding sites and has numerous genetic polymorphisms. The Km value of CYP2C9.2 for losartan oxidation reaction in vitro was similar to that of CYP2C9.1, but the Vmax value was about 50% lower than that of CYP2C9.1 regardless of the amounts of cytochrome P450 reductase and cytochrome b5 added in the reaction mixtures as redox partners. X-ray crystal structure of CYP2C9.2 in complex with losartan suggests that disruption of hydrogen bonds at a polymorphic locus, which is far away from the active center, leads to changes in the tertiary structure around the active center and access channels, as well as the orientation of ligand binding. Isothermal titration calorimetry experiments demonstrated that the interaction of CYP2C9 with losartan was enthalpy-dominated reaction with similar Kd values for CYP2C9.1 and CYP2C9.2.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、薬物代謝酵素CYP2C9を対象とし、そのモデル基質であるロサルタンを用いて、酵素の分子ダイナミクスとアロステリック性との相関の観点から、酵素活性発現機構、変異による代謝活性減弱機序を明らかにした。学術的意義として、CYP2C9*2を有する患者におけるロサルタン酸化活性の減弱機構に関する新規の知見を示し、種々の基質医薬品の代謝変化をもたらす一塩基多型の影響を解明するための解析法を提供した。これらの手法はCYP2C9以外のP450分子種とその基質医薬品との解析にも応用可能である。社会的意義として、薬物薬物相互作用の解析や代謝を考慮した新規医薬品候補物質の設計に有用な情報を提供した。
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Report
(6 results)
Research Products
(12 results)
