# Unraveling the metabolic potential and roles of reductases in the omicsynin biosynthetic gene cluster

## TL;DR

This study identifies the role of a specific reductase in the biosynthesis of omicsynins, revealing how it contributes to their antiviral properties.

## Contribution

The study demonstrates the essential role of the R domain of OmnF in forming the C-terminal aldehyde group of omicsynins.

## Key findings

- OmnF, not OmnG, is essential for omicsynin biosynthesis.
- FBMN analysis identified novel pseudo-tripeptide analogs lacking antiviral activity.
- The R domain of OmnF is crucial for the C-terminal aldehyde warhead formation.

## Abstract

Omicsynins are a group of pseudo-tetrapeptides produced by Streptomyces sp. 1647, which exhibited potent anti-influenza A virus and anti-coronavirus activities. However, its biosynthesis mechanism of C-terminus reduction remains unknown. In this work, we explored two short-chain dehydrogenase/reductase (SDR) superfamily encoding genes in the omicsynin biosynthetic gene cluster (BGC) and confirmed the necessity of omnF, rather than omnG, in the biosynthesis of omicsynins through gene deletion in vivo. Subsequently, Feature-Based Molecular Networking (FBMN) analysis revealed three pseudo-tetrapeptides with C-terminal carboxyl group and four unexpected analogues encoded by the omicsynin BGC in the omnF reductase (R) domain knockout mutant strain. This led to the isolation and structural characterization of a group of novel pseudo-tripeptide compounds. Compared to the known omicsynins, these pseudo-tripeptides lack the second amino acid unit and the C-terminal aldehyde group, and consequently lose their anti-coronavirus activity. In conclusion, our work highlights the effectiveness of FBMN in unveiling cryptic analogues and clearly underscores the essential role of the R domain of OmnF in the biosynthesis of the C-terminal aldehyde warhead.

The online version contains supplementary material available at 10.1007/s13659-025-00560-5.