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

Jingjun Mo, Asfandyar Sikandar, Haowen Zhao, Ghader Bashiri, Liujie Huo, Martin Empting, Rolf Müller and Chengzhang Fu ()
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Jingjun Mo: Helmholtz Centre for Infection Research (HZI)
Asfandyar Sikandar: Helmholtz Centre for Infection Research (HZI)
Haowen Zhao: Helmholtz Centre for Infection Research (HZI)
Ghader Bashiri: Private Bag
Liujie Huo: Shandong University
Martin Empting: Helmholtz Centre for Infection Research (HZI)
Rolf Müller: Helmholtz Centre for Infection Research (HZI)
Chengzhang Fu: Helmholtz Centre for Infection Research (HZI)

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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 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 F420H2-dependent oxidoreductases and identify critical residues. Our findings uncover a unique statine biosynthetic pathway employing the only known iterative F420H2-dependent oxidoreductase to date.

Date: 2025
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DOI: 10.1038/s41467-025-59785-0

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