9G64 | pdb_00009g64

Tandem ketone reduction in pepstatin biosynthesis reveals an F 420 H 2 -dependent statine pathway.

(2025) Nat Commun 16: 4531-4531

• PubMed: 40374670 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41467-025-59785-0
• Primary Citation of Related Structures:  
  9G64, 9GKH, 9GM0, 9GNC, 9GND


• PubMed 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 F ₄₂₀ H ₂ -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 statine by PepI contrasts with the previously hypothesized biosynthesis involving polyketide synthase ketoreductase domains. Structural studies, site-directed mutagenesis, and deuterium-labeled enzyme assays probe the mechanism of F ₄₂₀ H ₂ -dependent oxidoreductases and identify critical residues. Our findings uncover a unique statine biosynthetic pathway employing the only known iterative F ₄₂₀ H ₂ -dependent oxidoreductase to date.

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Organizational Affiliation: 

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.