Target Identification of Yaku’amide B and Its Two Distinct Activities against Mitochondrial FoF1-ATP Synthase
| Autor: | Masayuki Inoue, Shingo Dan, Kai Kitamura, Hiroaki Itoh, Kaori Sakurai |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
ATP synthase
biology 010405 organic chemistry Chemistry General Chemistry Mitochondrion 010402 general chemistry Subcellular localization 01 natural sciences Biochemistry Catalysis 0104 chemical sciences Colloid and Surface Chemistry Mechanism of action Cell culture Biotinylation medicine biology.protein Target protein medicine.symptom Mode of action |
| Zdroj: | Journal of the American Chemical Society. 140:12189-12199 |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | Yaku’amide B (1b) is a structurally unique tetradecapeptide bearing four β,β-dialkylated α,β-unsaturated amino acid residues. Growth-inhibitory profile of 1b against a panel of 39 human cancer cell lines is distinct from those of clinically used anticancer drugs, suggesting a novel mechanism of action. We achieved total syntheses of chemical probes based on 1b and elucidated the cellular target and mode of action of 1b. Fluorescent (3, 4) and biotinylated (5, 6) derivatives of 1b were prepared for cell imaging studies and pull-down assays, respectively. In addition, the unnatural enantiomer of 1b (ent-1b) and its fluorescent probe (ent-3) were synthesized for control experiments. Subcellular localization analysis using 3 and 4 showed that 1b selectively accumulates in the mitochondria of MCF-7 human breast cancer cells. Pull-down assays with 6 revealed FoF1-ATP synthase as the major target protein of 1b. Consistent with these findings, biochemical activity assays showed that 1b inhibits ATP production cat... |
| Databáze: | OpenAIRE |
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