Stereochemical Determination and Complex Biosynthetic Assembly of Etnangien, a Highly Potent RNA Polymerase Inhibitor from the Myxobacterium Sorangium cellulosum
Stereochemical Determination and Complex Biosynthetic Assembly of Etnangien, a Highly Potent RNA Polymerase Inhibitor from the Myxobacterium Sorangium cellulosum
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DOI：
10.1021/ja804194c
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发表时间：
2008-10-29
影响因子：
15
通讯作者：
Mueller, Rolf
中科院分区：
文献类型：
--
作者：
Menche, Dirk;Arikan, Fatih;Mueller, Rolf
天然大环内酯类抗生素etnangien，一种结构独特的RNA聚合酶抑制剂，从粘细菌，一个有效的新的类似物的报告。它可以很容易地从纤维堆囊菌的发酵液中获得，并显示出与etnangien相当的高抗生素活性。然而，它比众所周知的不稳定的真实天然产品本身更容易获得。重要的是，它在中性条件下是稳定的，允许精细的NMR测量用于分配12个羟基和甲基轴承立体中心。这些复杂的聚酮化合物的全部绝对和相对立体化学通过广泛的高场NMR研究的组合来确定，包括基于J的构型分析、分子建模和合成衍生化，并结合基于生物合成研究的创新方法。本文首次报道了这些大环内酯类抗生素的溶液构象和三维结构。最后，完整的生物合成基因簇进行了详细分析，揭示了一个非常不寻常的和复杂的反式AT型聚酮生物合成，它不遵循共线性规则，最有可能执行编程迭代以及模块跳跃，并表现出HMG-CoA盒定向甲基化。
A potent novel analogue of the natural macrolide antibiotic etnangien, a structurally unique RNA polymerase inhibitor from myxobacteria, is reported. It may be readily obtained from fermentation broths of Sorangium cellulosum and shows high antibiotic activity, comparable to that of etnangien. However, it is much more readily available than the notoriously labile authentic natural product itself. Importantly, it is stable under neutral conditions, allowing for elaborate NMR measurements for assignment of the 12 hydroxyl- and methyl-bearing stereogenic centers. The full absolute and relative stereochemistries; of these complex polyketides were determined by a combination of extensive high-field NMR studies, including J-based configuration analysis, molecular modeling, and synthetic derivatization in Combination with an innovative method based on biosynthetic studies of this polyketide which is also presented here. A first look into the solution conformation and 3D structure of these promising macrolide antibiotics is reported. Finally, the complete biosynthetic gene cluster was analyzed in detail, revealing a highly unusual and complex trans-AT type polyketide biosynthesis, which does not follow colinearity rules, most likely performs programmed iteration as well as module skipping, and exhibits HMG-CoA box-directed methylation.