Biosynthesis of the β-Lactone Proteasome Inhibitors Belactosin and Cystargolide.
Felix WolfJudith S BauerTheresa M BendelAndreas KulikJörn KalinowskiHarald GrossLeonard KaysserPublished in: Angewandte Chemie (International ed. in English) (2017)
Belactosins and cystargolides are natural product proteasome inhibitors from Actinobacteria. Both feature dipeptidic backbones and a unique β-lactone building block. Herein, we present a detailed investigation of their biosynthesis. Identification and analysis of the corresponding gene clusters indicated that both compounds are assembled by rare single-enzyme amino acid ligases. Feeding experiments with isotope-labeled precursors and in vitro biochemistry showed that the formation of the β-lactone warhead is unprecedented and reminiscent of leucine biosynthesis, and that it involves the action of isopropylmalate synthase homologues.