Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Stefan-Meier-Straße 19, 79104 Freiburg, Germany.
Faculty of Biology, Schänzlestraße 1, 79104 Freiburg, Germany.
J Am Chem Soc. 2020 Apr 1;142(13):5913-5917. doi: 10.1021/jacs.9b12736. Epub 2020 Mar 19.
The structural diversity of type II polyketides is largely generated by tailoring enzymes. In rishirilide biosynthesis by , C-labeling studies previously implied extraordinary carbon backbone and side-chain rearrangements. In this work, we employ gene deletion experiments and enzyme studies to identify key biosynthetic intermediates and expose intricate redox tailoring steps for the formation of rishirilides A, B, and D and lupinacidin A. First, the flavin-dependent RslO5 reductively ring-opens the epoxide moiety of an advanced polycyclic intermediate to form an alcohol. Flavin monooxygenase RslO9 then oxidatively rearranges the carbon backbone, presumably via lactone-forming Baeyer-Villiger oxidation and subsequent intramolecular aldol condensation. While RslO9 can further convert the rearranged intermediate to rishirilide D and lupinacidin A, an additional ketoreductase RslO8 is required for formation of the main products rishirilide A and rishirilide B. This work provides insight into the structural diversification of aromatic polyketide natural products via unusual redox tailoring reactions that appear to defy biosynthetic logic.
II 型聚酮化合物的结构多样性主要是由修饰酶产生的。在 通过生物合成 rishirilide 时，之前的 C 标记研究表明存在非凡的碳骨架和侧链重排。在这项工作中，我们采用基因缺失实验和 酶研究来鉴定关键的生物合成中间体，并揭示形成 rishirilide A、B 和 D 以及 lupinacidin A 的复杂氧化还原修饰步骤。首先，黄素依赖性 RslO5 将环氧部分还原开环，形成醇。黄素单加氧酶 RslO9 然后通过内酯形成 Baeyer-Villiger 氧化和随后的分子内醛缩合作用氧化重排碳骨架。虽然 RslO9 可以进一步将重排的中间体转化为 rishirilide D 和 lupinacidin A，但需要额外的酮还原酶 RslO8 才能形成主要产物 rishirilide A 和 rishirilide B。这项工作提供了对通过不寻常的氧化还原修饰反应进行的芳香聚酮天然产物结构多样化的深入了解，这些反应似乎违反了生物合成逻辑。
