Sugimoto Yuki, Ishida Keishi, Traitcheva Nelly, Busch Benjamin, Dahse Hans-Martin, Hertweck Christian
Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.
Chem Biol. 2015 Feb 19;22(2):229-40. doi: 10.1016/j.chembiol.2014.12.014. Epub 2015 Feb 5.
Many pharmacologically important natural products are assembled by modular type I polyketide synthases (PKS), which typically act in a unidirectional fashion. The synthases producing the unusual nitro-substituted polyketides neoaureothin (nor, also called spectinabilin) and aureothin (aur) are exceptional, as they employ individual modules iteratively. Here, we investigate the plasticity of the nor PKS and the factors governing the number of elongations catalyzed by the noncanonical module. Surprisingly, we observe that the nor PKS can mediate an additional chain elongation to yield the higher homolog homoneoaureothin. Furthermore, we design several truncated variants of the nor PKS to use them in the context of artificial assembly lines for aureothin and homoaureothin. The resulting polypropionate derivatives provide valuable insights into chain length control and reveal structure-activity relationships relating to the size of the polypropionate backbones. Overall, we show that iterative modules are remarkably adaptable while downstream modules are gatekeepers that select for correct polyketide chain length.
许多具有重要药理活性的天然产物是由模块化的I型聚酮合酶（PKS）组装而成，这些酶通常以单向方式起作用。产生不寻常的硝基取代聚酮化合物新金硫素（nor，也称为壮观素）和金硫素（aur）的合成酶则是例外，因为它们会反复使用单个模块。在此，我们研究了nor PKS的可塑性以及控制非典型模块催化延伸次数的因素。令人惊讶的是，我们发现nor PKS可以介导额外的链延伸，以产生更高同系物高同新金硫素。此外，我们设计了nor PKS的几种截短变体，以便在用于金硫素和高同金硫素的人工装配线中使用。由此产生的聚丙酸酯衍生物为链长控制提供了有价值的见解，并揭示了与聚丙酸酯主链大小相关的构效关系。总体而言，我们表明迭代模块具有显著的适应性，而下游模块则是选择正确聚酮链长度的守门人。
