The dual mode of action of bistramide A entails severing of filamentous actin and covalent protein modification.
The dual mode of action of bistramide A entails severing of filamentous actin and covalent protein modification.
复制标题
bistramide A 的双重作用模式需要丝状肌动蛋白的切断和共价蛋白修饰。
DOI：
10.1073/pnas.0710727105
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发表时间：
2008
影响因子：
11.1
通讯作者：
Kozmin,SergeyA
中科院分区：
文献类型：
--
作者：
Rizvi,SyedAlipayam;Courson,DavidS;Keller,ValerieA;Rock,RonaldS;Kozmin,SergeyA
这项研究全面描述了双肠酰胺A的作用模式，并确定了双肠酰胺类化合物的结构要求，这些化合物在体内外负责切断肌动蛋白细丝和抑制癌细胞的生长。我们合理地设计和组装了一系列天然产物的结构类似物，包括荧光标记的共轭化合物。我们使用TIRF显微镜直接观察到肌动蛋白细丝被这一系列小分子切断，这证实了螺酮和酰胺亚基的结合足以使肌动蛋白细丝在体外快速分解。此外，我们还证明了双肠酰胺A的烯酮亚基负责对A549细胞中的蛋白质进行共价修饰，从而进一步提高了天然产物的细胞毒性。我们的结果表明，双乙酰胺A通过切断肌动蛋白细丝和共价固定细胞内单体肌动蛋白的双重作用机制而产生其强大的抗增殖活性。
This study provides comprehensive characterization of the mode of action of bistramide A and identifies structural requirements of bistramide-based compounds that are responsible for severing actin filaments and inhibiting growth of cancer cellsin vitroandin vivo. We rationally designed and assembled a series of structural analogs of the natural product, including a fluorescently labeled conjugate. We used TIRF microscopy to directly observe actin filament severing by this series of small molecules, which established that the combination of the spiroketal and the amide subunits was sufficient to enable rapid actin filament disassemblyin vitro. In addition, we demonstrated that the enone subunit of bistramide A is responsible for covalent modification of the proteinin vitroand in A549 cells, resulting in further increase in the cytotoxicity of the natural product. Our results demonstrate that bistramide A elicits its potent antiproliferative activity by a dual mechanism of action, which entails both severing of actin filaments and covalent sequestration of monomeric actin in the cell.