Biomimetic Total Synthesis and Paired Omics Identify an Intermolecular Diels-Alder Reaction as the Key Step in Lugdunomycin Biosynthesis.

ABSTRACT: Microbial natural products are the basis of the majority of clinical drugs, where the discovery of truly novel structural scaffolds to fill the discovery pipelines is a prerequisite. Lugdunomycin is a highly rearranged angucycline polyketide produced by Streptomyces sp. QL37, with an enigmatic biosynthetic pathway. Here we show that lugdunomycin is formed by a rare intermolecular Diels-Alder reaction, with elmonin as a masked diene and iso-maleimycin as a dienophile. Genomics, mutational analysis, and heterologous expression revealed that the biosynthesis of the substrates is encoded by distinct biosynthetic gene clusters (BGCs), whereby elmonin is specified by an angucycline BGC, while the biosynthesis of iso-maleimycin is encoded by a BGC for a β-lactone-like compoun

SUBMITTER: Uiterweerd MT 

PROVIDER: S-EPMC12022981 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature