2. Academic Validation
  3. Discovery of a Cryptic Nitro Intermediate in the Biosynthesis of the 3-(trans-2'-Aminocyclopropyl)alanine Moiety of Belactosin A

Discovery of a Cryptic Nitro Intermediate in the Biosynthesis of the 3-(trans-2'-Aminocyclopropyl)alanine Moiety of Belactosin A

  • Org Lett. 2022 Jan 21;24(2):736-740. doi: 10.1021/acs.orglett.1c04205.
Alicia Engelbrecht 1 2,  Felix Wolf 1 2,  Annika Esch 3 4,  Andreas Kulik 3,  Sergei I Kozhushkov 5,  Armin de Meijere 5,  Chambers C Hughes 2 3 4,  Leonard Kaysser 1 2 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Biology, University of Tübingen, 72076 Tübingen, Germany.
  • 2 German Center for Infection Research, Partner Site Tübingen, 72076 Tübingen, Germany.
  • 3 Department of Microbial Bioactive Compounds, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany.
  • 4 Cluster of Excellence EXC 2124: Controlling Microbes to Fight Infection, University of Tübingen, 72076 Tübingen, Germany.
  • 5 Institute for Organic and Biomolecular Chemistry, University of Göttingen, 37077 Göttingen, Germany.
  • 6 Institute for Drug Discovery, Department of Pharmaceutical Biology, University of Leipzig, 04317 Leipzig, Germany.
PMID: 34990553 DOI: 10.1021/acs.orglett.1c04205
Abstract

Belactosin A, a β-lactone Proteasome Inhibitor, contains a unique 3-(trans-2'-aminocyclopropyl)alanine moiety. We recently identified the biosynthetic gene cluster of the belactosin series from Streptomyces sp. UCK14. To shed light on the formation of the aminocyclopropylalanine, we established a heterologous pathway expression, constructed a set of gene deletion mutants, and performed feeding studies for a chemical complementation that include the incorporation of stable isotope-labeled precursors. We thereby show that, in the biosynthesis of this building block, a cryptic nitrocyclopropylalanine intermediate is generated from l-lysine. The subsequent reduction of the N-oxygenated precursor to the corresponding amine is mediated by the molybdopterin-dependent Enzyme BelN.

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