2020 Fiscal Year Final Research Report
Mechanism of aggregation of ADP/ATP carrier induced by epoxycyclohexenedione (ECHD)-type inhibitor
| Project/Area Number |
18K05458
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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 38040:Bioorganic chemistry-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
山本 武範 国立医薬品食品衛生研究所, 遺伝子医薬部, 主任研究官 (80457324)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | ミトコンドリア / ADP/ATP輸送体 / ECHD類 / ケミカルバイオロジー |
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| Outline of Final Research Achievements |
We found epoxycyclohexenedione (ECHD)-type compounds as unique inhibitors of the bovine heart mitochondrial ADP/ATP carrier (AAC). Proteomic analyses of ECHD-bound AAC as well as biochemical characterization using different SH reagents showed that ECHDs inhibit the function of AAC by covalently binding primarily to Cys57 and secondarily to Cys160. Interestingly, AAC remarkably aggregated in SMPs upon being incubated with high concentrations of ECHDs for a long period of time. ECHDs are the first chemicals, to the best of our knowledge, to induce prominent structural alteration in AAC without forming intermolecular S－S linkages. When all solvent accessible cysteines (Cys57, Cys160, and Cys257) were previously modified by N-ethylmaleimide, the aggregation of AAC was completely suppressed. In contrast, when Cys57 or Cys160 is selectively modified by a SH reagent, the covalent binding of ECHDs to a residual free residue of the two cysteines is sufficient to induce aggregation.
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| Free Research Field |
農芸化学・生物有機化学
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| Academic Significance and Societal Importance of the Research Achievements |
ミトコンドリアADP/ATP輸送体(AAC)は、ミトコンドリア内膜上でADPとATPの交換輸送を行う分子質量約30 kDaの膜輸送体である。AACは細胞のエネルギー代謝の要となる膜輸送体であるため、本輸送体の特異的阻害剤に関する研究は、エネルギー代謝を制御する新規な薬剤の開発研究に資するところが大きい。申請者は、既知のAAC阻害剤であるBKA類やCATR類と分子骨格の異なるエポキシシクロヘキセンジオン類（ECHD類）がAACの新規な阻害剤であることを見出した。本化合物は、細胞のエネルギー代謝を標的とする新たな医農薬シーズとしての可能性を秘めている。
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