α-Ketoglutarate-Dependent Dioxygenase-Catalyzed Macrocyclization in RiPPs

作者：Yinzheng Xia, Ying Shi, Zhixi Xiao, Xiangqian Xie, Boning Wang, Hongwei Yao, Huan Wang · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.5c07332 · 被引用次数：9 · 研究领域：Microbial Natural Products and Biosynthesis、Chemical Synthesis and Analysis、Synthetic Organic Chemistry Methods

α-Ketoglutarate-dependent dioxygenases (αKGDs) are versatile biocatalysts for oxidative reactions, yet their role in ribosomally synthesized and post-translationally modified peptide (RiPP) macrocyclization remains unexplored. In this study, we uncover the widespread co-occurrence of JmjC domain-containing αKGDs (JMJDs) with diverse RiPP subfamilies in biosynthetic gene clusters (BGCs) through bioinformatic analysis. Specifically, we identify a conserved group of class II lanthipeptide BGCs encoding a two-component JMJD pair. As a representative example, heterologous reconstitution of the cor BGC from Streptomyces corchorusii, encoding a class II lanthipeptide synthetase CorM and the αKGD pair CorB–CorD, yields the metal-binding lanthipeptide corsin, which features a methyllanthionine (MeLan) ring and a unique Cys(S)-Tyr(Cβ) cross-link. Functional studies reveal that CorM installs a MeLan ring in the precursor peptide CorA, while the CorB–CorD pair catalyzes oxidative Cys(S)-Tyr(Cβ) cross-linking. Mechanistic investigations demonstrate that CorD, a canonical JMJD, catalyzes the Tyr7 Cβ-H abstraction and generates a para -quinone methide ( p QM) intermediate, which undergoes Michael addition with Cys3. CorB, an inactive JMJD homologue, is essential for catalysis, unveiling a unique two-component αKGD system. This work expands the RiPP enzymatic toolkit by introducing αKGDs as radical catalysts for macrocyclization and advances our understanding of the diverse enzymatic strateg...