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首页> 外文期刊>The Journal of Antibiotics: An International Journal >FR177391, a new anti-hyperlipidemic agent from Serratia. IV. Target identification and validation by chemical genetic approaches.
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FR177391, a new anti-hyperlipidemic agent from Serratia. IV. Target identification and validation by chemical genetic approaches.

机译：FR177391，Serratia的新型抗高血脂药。 IV。通过化学遗传方法进行目标识别和验证。

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摘要

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.
机译：具有独特生物活性的天然产物是剖析生物学新途径的非常有前途的分子探针。获得细菌产物FR177391，其为具有抗高血脂作用的天然化合物。 FR177391增强了肥胖的非胰岛素依赖性糖尿病动物模型C57BL / KsJ-db / db小鼠的小鼠3T3-L1成纤维细胞向脂肪细胞的分化，并降低了甘油三酸酯的循环水平，尽管其作用机理尚不清楚。我们在这里报告通过使用亲和色谱法，FR177391的目标蛋白被鉴定为蛋白磷酸酶2A（PP2A）。 FR177391在纳摩尔浓度下有效抑制PP2A活性，并与磷酸酶抑制剂冈田酸共享其结合口袋。除表型改变外，在FR177391处理的3T3-L1细胞中还观察到了细胞外信号调节激酶（ERK）蛋白磷酸化的增强。这些结果表明，由于PP2A抑制ERK蛋白的去磷酸化，延长了ERK蛋白的活化在脂肪细胞成熟和调节血脂方面起着重要作用。

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