title: Iejimalides show anti-osteoclast activity via V-ATPase inhibition.
abstract: 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.
authors.affiliation: Antibiotics Laboratory, RIKEN Discovery Research Institute, Hirosawa, Saitama.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kazami
authors.forename: Makoto
authors.initials: M
authors.lastname: Muroi
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kubota
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.forename: Jun'ichi
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D021122:Protein Subunits; D013912:Threonine; D025262:Vacuolar Proton-Translocating ATPases