Tandem ketone reduction in pepstatin biosynthesis reveals an F₄₂₀H₂-dependent statine pathway.

ABSTRACT: Pepstatins are potent inhibitors of aspartic proteases, featuring two statine residues crucial for target binding. However, the biosynthesis of pepstatins, especially their statine substructure, remains elusive. Here, we discover and characterize an unconventional gene cluster responsible for pepstatin biosynthesis, comprising discrete nonribosomal peptide synthetase and polyketide synthase genes, highlighting its trans-acting and iterative nature. Central to this pathway is PepI, an F₄₂₀H₂-dependent oxidoreductase. The biochemical characterization of PepI reveals its role in the tandem reduction of β-keto pepstatin intermediates. PepI first catalyzes the formation of the central statine, then produces the C-terminal statine moiety. The post-assembly-line formation of

SUBMITTER: Mo J 

PROVIDER: S-EPMC12081711 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature