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首页> 外文期刊>Biochemistry >Inhibition of protein synthesis by didemnin B: how EF-1alpha mediates inhibition of translocation.
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Inhibition of protein synthesis by didemnin B: how EF-1alpha mediates inhibition of translocation.

机译：迪地美宁B对蛋白质合成的抑制作用：EF-1alpha如何介导对转运的抑制作用。

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摘要

The antineoplastic cyclic depsipeptide didemnin B (DB) inhibits protein synthesis in cells and in vitro. The stage at which DB inhibits protein synthesis in cells is not known, although dehydrodidemnin B arrests translation at the stage of polypeptide elongation. Inhibition of protein synthesis by DB in vitro also occurs at the elongation stage, and it was shown previously that DB prevents EF-2-dependent translocation in partial reaction models of protein synthesis. This inhibition of translocation displays an absolute requirement for EF-1alpha; however, the dependence upon EF-1alpha was previously unexplained. It is shown here that DB binds only weakly to EF-1alpha/GTP in solution, but binds to ribosome. EF-1alpha complexes with a dissociation constant K(d) = 4 microM. Thus, the inhibition of protein synthesis by DB appears to involve an interaction with both EF-1alpha and ribosomes in which all three components are required. Using diphtheria toxin-mediated ADP-ribosylation to assay for EF-2, it is demonstrated that DB blocks EF-2 binding to pre-translocative ribosome.EF-1alpha complexes, thus preventing ribosomal translocation. Based on this model for protein synthesis inhibition by DB, and the proposed mechanism of action of fusidic acid, evidence is presented in support of the Grasmuk model for EF-1alpha function in which this elongation factor does not fully depart the ribosome during polypeptide elongation.
机译：抗肿瘤环状双缩肽二氢辅酶B（DB）抑制细胞和体外的蛋白质合成。 DB抑制细胞中蛋白质合成的阶段是未知的，尽管脱氢木糖蛋白B在多肽延长阶段会阻止翻译。 DB在体外对蛋白质合成的抑制也发生在延伸阶段，并且先前已证明DB在蛋白质合成的部分反应模型中阻止了EF-2依赖性易位。这种对易位的抑制显示了对EF-1alpha的绝对要求。但是，以前无法解释对EF-1alpha的依赖性。在此表明，DB在溶液中仅与EF-1alpha / GTP弱结合，而与核糖体结合。 EF-1alpha复合物的解离常数K（d）= 4 microM。因此，DB对蛋白质合成的抑制似乎涉及与EF-1α和核糖体的相互作用，其中需要全部三个成分。使用白喉毒素介导的ADP-核糖基化检测EF-2，证明DB阻断EF-2与易位核糖体EF-1α复合物的结合，从而阻止了核糖体易位。基于该DB抑制蛋白质合成的模型以及拟定的夫西地酸的作用机理，为支持EF-1α功能的Grasmuk模型提供了证据，在该模型中，这种延长因子并未在多肽延长过程中完全脱离核糖体。

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