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タイトル: | IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism |
著者: | Tsuji, Atsuhito Akao, Takumi Masuya, Takahiro https://orcid.org/0000-0003-4950-0527 (unconfirmed) Murai, Masatoshi https://orcid.org/0000-0001-6601-2854 (unconfirmed) Miyoshi, Hideto https://orcid.org/0000-0002-1792-554X (unconfirmed) |
著者名の別形: | 辻, 諄人 赤尾, 拓海 桝谷, 貴洋 村井, 正俊 三芳, 秀人 |
キーワード: | bioenergetics complex I mitochondria ubiquinone enzyme inhibitor chemical biology photoaffinity labeling cancer hypoxia IACS-010759 |
発行日: | 22-May-2020 |
出版者: | American Society for Biochemistry and Molecular Biology Inc. |
誌名: | Journal of Biological Chemistry |
巻: | 295 |
号: | 21 |
開始ページ: | 7481 |
終了ページ: | 7491 |
抄録: | The small molecule IACS-010759 has been reported to potently inhibit the proliferation of glycolysis-deficient hypoxic tumor cells by interfering with the functions of mitochondrial NADH-ubiquinone oxidoreductase (complex I) without exhibiting cytotoxicity at tolerated doses in normal cells. Considering the significant cytotoxicity of conventional quinone-site inhibitors of complex I, such as piericidin and acetogenin families, we hypothesized that the mechanism of action of IACS-010759 on complex I differs from that of other known quinone-site inhibitors. To test this possibility, here we investigated IACS-010759's mechanism in bovine heart submitochondrial particles. We found that IACS-010759, like known quinone-site inhibitors, suppresses chemical modification by the tosyl reagent AL1 of Asp¹⁶⁰ in the 49-kDa subunit, located deep in the interior of a previously proposed quinone-access channel. However, contrary to the other inhibitors, IACS-010759 direction-dependently inhibited forward and reverse electron transfer and did not suppress binding of the quinazoline-type inhibitor [¹²⁵I]AzQ to the N terminus of the 49-kDa subunit. Photoaffinity labeling experiments revealed that the photoreactive derivative [¹²⁵I]IACS-010759-PD1 binds to the middle of the membrane subunit ND1 and that inhibitors that bind to the 49-kDa or PSST subunit cannot suppress the binding. We conclude that IACS-010759's binding location in complex I differs from that of any other known inhibitor of the enzyme. Our findings, along with those from previous study, reveal that the mechanisms of action of complex I inhibitors with widely different chemical properties are more diverse than can be accounted for by the quinone-access channel model proposed by structural biology studies. |
著作権等: | © 2020 Tsuji et al. This is an Open Access article under the Creative Commons Attribution 4.0 International license. |
URI: | http://hdl.handle.net/2433/275652 |
DOI(出版社版): | 10.1074/jbc.RA120.013366 |
PubMed ID: | 32295842 |
出現コレクション: | 学術雑誌掲載論文等 |
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