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

• DOI: 10.1021/acs.orglett.1c04205
• Publication Date: 2022-01-06T23:29:36Z
• Authors: Alicia Engelbrecht; Felix Wolf; Annika Esch; Andreas Kulik; Sergei I. Kozhushkov; Armin de Meijere; Chambers C. Hughes; Leonard Kaysser
• Keywords: Chemical Sciences not elsewhere classified; 572; Physiology; recently identified; cryptic nitrocyclopropylalanine intermediate; Plant Biology; cryptic nitro intermediate; 3 ‑(<; Biochemistry; Microbiology; alanine moiety; 01 natural sciences; thereby show; Virology; Genetics; stable isotope; lactone proteasome inhibitor; unique 3 -(<; gene deletion mutants; building block; biosynthetic gene cluster; corresponding amine; heterologous pathway expression; streptomyces </; 540; subsequent reduction; 0104 chemical sciences; chemical complementation; Infectious Diseases; labeled precursors; shed light; dependent enzyme beln; trans </; performed feeding studies; oxygenated precursor; Developmental Biology

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.