IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism
| Autor: | Takumi Akao, Atsuhito Tsuji, Masatoshi Murai, Hideto Miyoshi, Takahiro Masuya |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein subunit enzyme inhibitor chemical biology Mitochondrion bioenergetics Biochemistry Mitochondria Heart IACS-010759 03 medical and health sciences Piperidines Oxidoreductase Neoplasms ubiquinone medicine Animals Humans cancer Submitochondrial particle Molecular Biology chemistry.chemical_classification Oxadiazoles Electron Transport Complex I 030102 biochemistry & molecular biology biology Photoaffinity labeling complex I hypoxia Chemistry Cell Biology Cell Hypoxia Neoplasm Proteins Cell biology mitochondria 030104 developmental biology Enzyme Mechanism of action Enzyme inhibitor biology.protein Cattle medicine.symptom Glycolysis photoaffinity labeling |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| Popis: | 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 Asp(160) 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 [(125)I]AzQ to the N terminus of the 49-kDa subunit. Photoaffinity labeling experiments revealed that the photoreactive derivative [(125)I]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. |
| Databáze: | OpenAIRE |
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