Iejimalides Show Anti-Osteoclast Activity via V-ATPase Inhibition
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Iejimalides (IEJLs), 24-membered macrolides, are potent antitumor compounds, but their molecular targets remain to be revealed. In the course of screening, we identified IEJLs as potent osteoclast inhibitors. Since it is known that osteoclasts are sensitive to vacuolar H<SUP>+</SUP>-ATPase (V-ATPase) inhibitor, we investigated the effect of IEJLs on V-ATPases. IEJLs inhibited the V-ATPases of both mammalian and yeast cells <I>in situ</I>, and of yeast V-ATPases <I>in vitro</I>. A bafilomycin-resistant yeast mutant conferred IEJL resistance, suggesting that IEJLs bind a site similar to the bafilomycins/concanamycins-binding site. These results indicate that IEJLs are novel V-ATPase inhibitors, and that antitumor and antiosteporotic activities are exerted <I>via</I> V-ATPase inhibition.
- Agricultural and Biological Chemistry
Agricultural and Biological Chemistry 70(6), 1364-1370, 2006-06-23
Japan Society for Bioscience, Biotechnology, and Agrochemistry