title: FR177391, a new anti-hyperlipidemic agent from Serratia. IV. Target identification and validation by chemical genetic approaches.
abstract: Natural products with distinct biological activities are very promising molecular probes to dissect the novel pathways of biology. FR177391, a product of bacteria, was obtained as a natural compound possessing anti-hyperlipidemic effects. FR177391 enhances differentiation of mouse 3T3-L1 fibroblasts to adipocytes and reduces the circulating levels of triglyceride in C57BL/KsJ-db/db mice, a obese non-insulin-dependent diabetes mellitus animal model, although its mechanism of actions remained to be unknown. We report here that the target protein for FR177391 was identified to be protein phosphatase 2A (PP2A) by employing the method of affinity chromatography. FR177391 potently inhibited PP2A activity at nano molar concentration, and shared its binding pocket with a phosphatase inhibitor, okadaic acid. In addition to the phenotypic alterations, the enhancement for phosphorylation of extracellular signal-regulated kinase (ERK) protein was observed in the FR177391-treated 3T3-L1 cells. These results suggest that prolonged activation of ERK protein due to inhibition of its dephosphorylation by PP2A plays an important role in adipocyte maturation and regulation of the blood revels of lipids.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sato
authors.forename: Motoo
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Nishio
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohkubo
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujii
authors.forename: Hidenori
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D012705:Serratia / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents