State Key Laboratory of Microbial Resources & CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
State Key Laboratory of Microbial Resources & CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
Biochem Biophys Res Commun. 2021 Mar 5;543:8-14. doi: 10.1016/j.bbrc.2021.01.042. Epub 2021 Jan 23.
Paulomycins (PAUs) refer to a group of glycosylated antibiotics with attractive antibacterial activities against Gram-positive bacteria. They contain a special ring A moiety that is prone to dehydrate between C-4 and C-5 to a quinone-type form at acidic condition, which will reduce the antibacterial activities of PAUs significantly. Elucidation of the biosynthetic mechanism of the ring A moiety may facilitate its structure modifications by combinatorial biosynthesis to generate PAU analogues with enhanced bioactivity or stability. Previous studies showed that the ring A moiety is derived from chorismate, which is converted to 3-hydroxyanthranilic acid (3-HAA) by a 2-amino-2-deoxyisochorismate (ADIC) synthase, a 2,3-dihydro-3-hydroxyanthranilic acid (DHHA) synthase, and a DHHA dehydrogenase. Unfortunately, little is known about the conversion process from 3-HAA to the highly decorated ring A moiety of PAUs. In this work, we characterized Pau17 as an unprecedented 3-HAA 6-hydroxylase responsible for the conversion of 3-HAA to 3,6-DHAA by in vivo and in vitro studies, pushing one step forward toward elucidating the biosynthetic mechanism of the ring A moiety of PAUs.
保罗霉素（PAUs）属于一组具有吸引力的抗革兰氏阳性菌抗生素，它们含有一个特殊的环 A 部分，在酸性条件下，该部分容易在 C-4 和 C-5 之间脱水形成醌型，这将显著降低 PAUs 的抗菌活性。阐明环 A 部分的生物合成机制，可以通过组合生物合成来促进其结构修饰，生成具有增强的生物活性或稳定性的 PAU 类似物。先前的研究表明，环 A 部分来源于分支酸，分支酸通过 2-氨基-2-脱氧异分支酸（ADIC）合酶、2,3-二氢-3-羟基邻氨基苯甲酸（DHHA）合酶和 DHHA 脱氢酶转化为 3-羟基邻氨基苯甲酸（3-HAA）。然而，对于 3-HAA 到 PAUs 高度修饰的环 A 部分的转化过程，我们知之甚少。在这项工作中，我们通过体内和体外研究，鉴定了 Pau17 为一种前所未有的 3-HAA 6-羟化酶，负责将 3-HAA 转化为 3,6-DHAA，这为阐明 PAUs 环 A 部分的生物合成机制向前推进了一步。
