Helmholtz-Institute for Pharmaceutical Research Saarland, Actinobacteria Metabolic Engineering Group, UdS Campus, C2 3, 66123 Saarbrücken (Germany).
Angew Chem Int Ed Engl. 2015 Feb 9;54(7):2280-4. doi: 10.1002/anie.201408901. Epub 2014 Dec 23.
Pamamycins are macrodiolides of polyketide origin with antibacterial activities. Their biosynthesis has been proposed to utilize succinate as a building block. However, the mechanism of succinate incorporation into a polyketide was unclear. Here, we report identification of a pamamycin biosynthesis gene cluster by aligning genomes of two pamamycin-producing strains. This unique cluster contains polyketide synthase (PKS) genes encoding seven discrete ketosynthase (KS) enzymes and one acyl-carrier protein (ACP)-encoding gene. A cosmid containing the entire set of genes required for pamamycin biosynthesis was successfully expressed in a heterologous host. Genetic and biochemical studies allowed complete delineation of pamamycin biosynthesis. The pathway proceeds through 3-oxoadipyl-CoA, a key intermediate in the primary metabolism of the degradation of aromatic compounds. 3-Oxoadipyl-CoA could be used as an extender unit in polyketide assembly to facilitate the incorporation of succinate.
帕马霉素是聚酮类来源的大环内酯类抗生素，具有抗菌活性。其生物合成被认为利用琥珀酸作为构建块。然而，琥珀酸掺入聚酮的机制尚不清楚。在这里，我们通过比对两种产生帕马霉素的菌株的基因组，鉴定了一个帕马霉素生物合成基因簇。这个独特的簇包含聚酮合酶（PKS）基因，编码七个离散的酮合酶（KS）酶和一个酰基载体蛋白（ACP）编码基因。含有帕马霉素生物合成所需的整套基因的科斯米德在异源宿主中成功表达。遗传和生化研究允许对帕马霉素生物合成进行完全描绘。该途径经过 3-氧代己二酸 - CoA，这是芳香族化合物降解的主要代谢中的关键中间体。3-氧代己二酸 - CoA 可以用作聚酮组装中的扩展单元，以促进琥珀酸的掺入。
