Khosla Chaitan
Stanford University, Stanford, California 94305-5080, USA.
J Org Chem. 2009 Sep 4;74(17):6416-20. doi: 10.1021/jo9012089.
Nearly a quarter-century ago, the advent of molecular genetic tools in the field of natural product biosynthesis led to the remarkable revelation that the genes responsible for the biosynthesis, regulation, and self-resistance of complex polyketide antibiotics were clustered in the genomes of the bacteria that produced these compounds. This in turn facilitated rapid cloning and sequencing of genes encoding a number of polyketide synthases (PKSs). By now, it is abundantly clear that, notwithstanding extraordinary architectural and biocatalytic diversity, all PKSs are evolutionarily related enzyme assemblies. As such, understanding the molecular logic for the biosynthesis of literally thousands of amazing polyketide natural products made by nature can benefit enormously from detailed investigations into a few "model systems". For nearly the past two decades, our laboratory has focused its efforts on two such PKSs. One of them synthesizes two polyketides in approximately equal ratios, SEK4 and SEK4b, and both shunt products from the pathway that leads to the biosynthesis of the pigmented antibiotic actinorhodin. The other synthesizes 6-deoxyerythronolide B, the first isolable intermediate in the biosynthetic pathway for the widely used antibacterial agent erythromycin. Our present-day knowledge of the structures and mechanisms of these two PKSs is summarized here.
近四分之一个世纪前，分子遗传学工具在天然产物生物合成领域的出现带来了一个重大发现，即负责复杂聚酮类抗生素生物合成、调控和自身抗性的基因聚集在产生这些化合物的细菌基因组中。这反过来又促进了编码多种聚酮合酶（PKSs）的基因的快速克隆和测序。如今，很明显，尽管聚酮合酶具有非凡的结构和生物催化多样性，但它们都是进化上相关的酶组装体。因此，深入研究一些“模型系统”将极大地有助于理解自然界中由数千种惊人的聚酮类天然产物的生物合成的分子逻辑。在过去近二十年里，我们实验室一直致力于研究两种这样的聚酮合酶。其中一种以大致相等的比例合成两种聚酮化合物，即SEK4和SEK4b，它们都是通往色素抗生素放线紫红素生物合成途径的分流产物。另一种则合成6-脱氧红霉内酯B，它是广泛使用的抗菌剂红霉素生物合成途径中第一个可分离的中间体。本文总结了我们目前对这两种聚酮合酶的结构和机制的认识。
