Formicamycin biosynthesis involves a unique reductive ring contraction.
Formicamycin biosynthesis involves a unique reductive ring contraction.
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DOI：
10.1039/d0sc01712d
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发表时间：
2020-08-21
期刊：
影响因子：
8.4
通讯作者：
Wilkinson B
中科院分区：
文献类型：
--
作者：
Qin Z;Devine R;Booth TJ;Farrar EHE;Grayson MN;Hutchings MI;Wilkinson B
通过结合仿生化学和分子遗传学，我们证明福米霉素生物合成是通过还原法沃斯基反应进行的。法沙霉素天然产物是福米霉素的生物合成前体。两组化合物都是聚酮化合物天然产物，尽管表现出不同的三维拓扑结构，但仍表现出有效的抗菌活性。我们在此表明，法沙霉素转化为福米霉素代谢物需要两个基因产物，并通过一种新型的两步环扩张-环收缩途径发生。编码黄素依赖性单加氧酶的 forX 的缺失，消除了福米霉素的产生，并导致法沙霉素 E 的积累。编码黄素依赖性氧化还原酶的相邻基因 forY 的缺失，也消除了福米霉素的生物合成，并导致代表法沙霉素的 Baeyer-Villiger 氧化产物的新内酯代谢物的积累。这些结果将 ForX 确定为能够使法沙霉素的 C 环脱芳构化的 Baeyer-Villiger 单加氧酶。通过体内交叉喂养和仿生半合成实验，我们表明这些内酯产物代表生物合成中间体，在 ForY 催化的独特还原环收缩反应中被还原为福米霉素。
Using a combination of biomimetic chemistry and molecular genetics we demonstrate that formicamycin biosynthesis proceeds via reductive Favorskii-like reaction. Fasamycin natural products are biosynthetic precursors of the formicamycins. Both groups of compounds are polyketide natural products that exhibit potent antibacterial activity despite displaying different three-dimensional topologies. We show here that transformation of fasamycin into formicamycin metabolites requires two gene products and occurs via a novel two-step ring expansion-ring contraction pathway. Deletion of forX, encoding a flavin dependent monooxygenase, abolished formicamycin production and leads to accumulation of fasamycin E. Deletion of the adjacent gene forY, encoding a flavin dependent oxidoreductase, also abolished formicamycin biosynthesis and led to the accumulation of new lactone metabolites that represent Baeyer–Villiger oxidation products of the fasamycins. These results identify ForX as a Baeyer–Villiger monooxygenase capable of dearomatizing ring C of the fasamycins. Through in vivo cross feeding and biomimetic semi-synthesis experiments we showed that these lactone products represent biosynthetic intermediates that are reduced to formicamycins in a unique reductive ring contraction reaction catalyzed by ForY.