Iejimalides show anti-osteoclast activity via V-ATPase inhibition.
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(+)-ATPase (V-ATPase) inhibitor, we investigated the effect of IEJLs on V-ATPases. IEJLs inhibited the V-ATPases of both mammalian and yeast cells in situ, and of yeast V-ATPases in vitro. 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 via V-ATPase inhibition.
Kazami
Sayaka
S
Antibiotics Laboratory, RIKEN Discovery Research Institute, Hirosawa, Saitama.
Muroi
Makoto
M
Kawatani
Makoto
M
Kubota
Takaaki
T
Usui
Takeo
T
Kobayashi
Jun'ichi
J
Osada
Hiroyuki
H
D000818:Animals; D002478:Cells, Cultured; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D018942:Macrolides; D021122:Protein Subunits; D013912:Threonine; D025262:Vacuolar Proton-Translocating ATPases