Target Identification of Yaku'amide B and Its Two Distinct Activities against Mitochondrial Fo F1 -ATP Synthase

Journal of the American Chemical Society
Kai KitamuraMasayuki Inoue

Abstract

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 catalyzed by mitochondrial FoF1-ATP synthase. Remarkably, 1b was also found capable of enhancing the ATP hydrolytic activity of FoF1-ATP synthase. On the other hand, ent-1b inhibits ATP synthesis more weakly than does 1b and doe...Continue Reading

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Citations

Feb 7, 2020·Natural Product Reports·Anthony R CarrollMichèle R Prinsep
Jan 17, 2020·Angewandte Chemie·Hiroaki ItohMasayuki Inoue
Oct 7, 2020·Chemistry : a European Journal·Koichi KamiyaMasayuki Inoue
Dec 19, 2020·Angewandte Chemie·Yu CaiSteven L Castle
Dec 29, 2020·Cell Chemical Biology·Jaeyoung HaSeung Bum Park
Sep 18, 2020·European Journal of Medicinal Chemistry·Bhargav A PatelBrian S J Blagg
Jun 4, 2021·Journal of Natural Products·Koichi KamiyaMasayuki Inoue
Sep 1, 2020·ACS Chemical Biology·Takefumi KuranagaHideaki Kakeya

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