Biosynthesis of the β‐Lactone Proteasome Inhibitors Belactosin and Cystargolide. Issue 23 (28th April 2017)

• Record Type: Journal Article
• Authors: Wolf, Felix; Bauer, Judith S.; Bendel, Theresa M.; Kulik, Andreas; Kalinowski, Jörn; Gross, Harald; Kaysser, Leonard
• Is Part Of: Angewandte Chemie international edition. Volume 56:Issue 23(2017)
• Page Start: 6665
• Page End: 6668
• Publication Date: 2017-04-28
• Subjects: biosynthesis -- inhibitors -- lactones -- metabolism -- natural products; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201612076
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : Lactone synthesis : The biosynthesis of belactosins and cystargolides, which are peptidic β‐lactone proteasome inhibitors, follows an NRPS‐ and PKS‐independent pathway. The distinct β‐lactone moiety is assembled by isopropylmalate synthase like enzymes in a process that is reminiscent of leucine metabolism. The formation of the peptidic backbones is directed by discrete amino acid ligases.