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jbc.RA120.013366.pdf | 2.12 MB | Adobe PDF | 見る/開く |
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dc.contributor.author | Tsuji, Atsuhito | en |
dc.contributor.author | Akao, Takumi | en |
dc.contributor.author | Masuya, Takahiro | en |
dc.contributor.author | Murai, Masatoshi | en |
dc.contributor.author | Miyoshi, Hideto | en |
dc.contributor.alternative | 辻, 諄人 | ja |
dc.contributor.alternative | 赤尾, 拓海 | ja |
dc.contributor.alternative | 桝谷, 貴洋 | ja |
dc.contributor.alternative | 村井, 正俊 | ja |
dc.contributor.alternative | 三芳, 秀人 | ja |
dc.date.accessioned | 2022-07-28T23:47:20Z | - |
dc.date.available | 2022-07-28T23:47:20Z | - |
dc.date.issued | 2020-05-22 | - |
dc.identifier.uri | http://hdl.handle.net/2433/275652 | - |
dc.description.abstract | 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. | en |
dc.language.iso | eng | - |
dc.publisher | American Society for Biochemistry and Molecular Biology Inc. | en |
dc.rights | © 2020 Tsuji et al. | en |
dc.rights | This is an Open Access article under the Creative Commons Attribution 4.0 International license. | en |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | bioenergetics | en |
dc.subject | complex I | en |
dc.subject | mitochondria | en |
dc.subject | ubiquinone | en |
dc.subject | enzyme inhibitor | en |
dc.subject | chemical biology | en |
dc.subject | photoaffinity labeling | en |
dc.subject | cancer | en |
dc.subject | hypoxia | en |
dc.subject | IACS-010759 | en |
dc.title | IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism | en |
dc.type | journal article | - |
dc.type.niitype | Journal Article | - |
dc.identifier.jtitle | Journal of Biological Chemistry | en |
dc.identifier.volume | 295 | - |
dc.identifier.issue | 21 | - |
dc.identifier.spage | 7481 | - |
dc.identifier.epage | 7491 | - |
dc.relation.doi | 10.1074/jbc.RA120.013366 | - |
dc.textversion | publisher | - |
dc.identifier.pmid | 32295842 | - |
dcterms.accessRights | open access | - |
datacite.awardNumber | 18H02147 | - |
datacite.awardNumber | 19K22278 | - |
datacite.awardNumber | 18K05458 | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18H02147/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19K22278/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18K05458/ | - |
dc.identifier.pissn | 0021-9258 | - |
dc.identifier.eissn | 1083-351X | - |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.awardTitle | コレラ菌NADH-ユビキノン酸化還元酵素の阻害剤抵抗性メカニズムの解明 | ja |
jpcoar.awardTitle | ミトコンドリア呼吸鎖酵素からの活性酸素発生を遮断する化合物の創製 | ja |
jpcoar.awardTitle | エポキシシクロヘキセンジオン類によるADP/ATP輸送体の凝集メカニズムの解明 | ja |
出現コレクション: | 学術雑誌掲載論文等 |
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