National Academy of Sciences, Proceedings of the National Academy of Sciences, 16(114), p. 4135-4140, 2017
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Significance Despite significant advances in the prediction of natural product biosynthetic gene clusters (BGCs) from microbial genomes, challenges remain for those belong to the lesser-known classes. Using a bioactivity-guided library screening approach, we have identified a BGC encoding the biosynthesis of anisomycin, an important pyrrolidine-containing protein synthesis inhibitor. The biosynthetic pathway is distinct from known bacterial alkaloid pathways and involves a class of natural product backbone biosynthesis genes encoding an α-keto acid-incorporating transketolase. A cryptic but crucial glycosylation, unexpected transaminations, and a multistep pyrrolidine-forming reaction catalyzed by a single enzyme are also required to complete the assembly of the core benzylpyrrolidine scaffold. These findings open up new avenues for genomics-guided natural product discovery and engineering of pyrrolidine antibiotics.