The Marine Polyketide Myriaporone 3/4 Stalls Translation by Targeting the Elongation Phase
The Marine Polyketide Myriaporone 3/4 Stalls Translation by Targeting the Elongation Phase
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DOI：
10.1002/cbic.201200522
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发表时间：
2013-01
期刊：
影响因子：
3.2
通讯作者：
Yazh Muthukumar;M. Roy;A. Raja;Richard E. Taylor;F. Sasse
中科院分区：
文献类型：
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作者：
Yazh Muthukumar;M. Roy;A. Raja;Richard E. Taylor;F. Sasse
Myriaporone 3/4是一种细胞毒性聚酮化合物，已被报道为真核蛋白质合成的抑制剂。然而，它抑制翻译的机制尚不清楚。在这里，我们表明，myriaporone 3/4摊位蛋白质合成的延伸阶段，通过诱导真核细胞延伸因子2的磷酸化。磷酸化的结果，从直接结合的myriaporone 3/4真核细胞延伸因子2激酶。我们的研究还表明，纳摩尔范围内的myriaporone 3/4可抑制内皮细胞的体外试管形成，而无细胞毒性。一般来说，myriaporone 3/4对原代细胞的毒性比对肿瘤细胞的毒性低至少300倍。
Myriaporone 3/4, a cytotoxic polyketide, has been reported as an inhibitor of eukaryotic protein synthesis. However, the mechanism by which it inhibits translation was unknown. Here we show that myriaporone 3/4 stalls protein synthesis in the elongation phase by inducing phosphorylation of eukaryotic elongation factor 2. The phosphorylation results from direct binding of myriaporone 3/4 to eukaryotic elongation factor 2 kinase. Our study also shows that myriaporone 3/4 in the nanomolar range inhibits in vitro tube formation by endothelial cells without being cytotoxic. In general, myriaporone 3/4 was at least 300 times less toxic to primary cells than to tumor cells.