School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
Department of Plant Sciences and Plant Pathology, Montana State University, Bozeman, Montana 59717, United States.
ACS Chem Biol. 2022 Jun 17;17(6):1351-1356. doi: 10.1021/acschembio.2c00288. Epub 2022 Jun 8.
The bacterial modular type I polyketide synthases (PKSs) typically furnish nonaromatic lactone and lactam natural products. Here, by the complete enzymatic production of the polyketide antibiotic pyoluteorin, we describe the biosynthetic mechanism for the construction of an aromatic resorcylic ring by a type I PKS. We find that the pyoluteorin type I PKS does not produce an aromatic product, rather furnishing an alicyclic dihydrophloroglucinol that is later enzymatically dehydrated and aromatized. The aromatizing dehydratase is encoded in the pyoluteorin biosynthetic gene cluster (BGC), and its presence is conserved in other BGCs encoding production of pyrrolic polyketides. Sequence similarity and mutational analysis demonstrates that the overall structure and position of the active site for the aromatizing dehydratase is shared with flavin-dependent halogenases albeit with a loss in ability to perform redox catalysis. We demonstrate that the post-PKS dehydrative aromatization is critical for the antibiotic activity of pyoluteorin.
细菌模块化 I 型聚酮合酶 (PKSs) 通常提供非芳香族内酯和内酰胺天然产物。在这里，通过完全酶促生产聚酮抗生素吡鲁霉素，我们描述了 I 型 PKS 构建芳香族间苯二酚环的生物合成机制。我们发现吡鲁霉素 I 型 PKS 不会产生芳香族产物，而是生成一种脂环二氢间苯二酚，然后该化合物被酶促脱水并芳构化。芳构化脱水酶编码在吡鲁霉素生物合成基因簇 (BGC) 中，并且在编码吡咯类聚酮化合物生产的其他 BGC 中也保守存在。序列相似性和突变分析表明，尽管失去了氧化还原催化能力，但芳构化脱水酶的整体结构和活性位点位置与黄素依赖卤化酶共享。我们证明了后 PKS 脱水芳构化对于吡鲁霉素的抗生素活性至关重要。
