# Elucidation of the Verrucofortine Biosynthetic Pathway Enables Identification of a Cyclodipeptide Prenyltransferase with High Catalytic Efficiency

## TL;DR

Scientists discovered how a fungus makes a compound called verrucofortine and found a highly efficient enzyme that could be useful for modifying small molecules.

## Contribution

Identification of a cyclodipeptide prenyltransferase with high catalytic efficiency for biocatalytic applications.

## Key findings

- The biosynthetic pathway of verrucofortine was elucidated using gene deletion and biochemical analysis.
- VftPT exhibits higher catalytic efficiency than known homologues for prenylation of tryptophan-containing cyclodipeptides.
- VftPS assembles the cyclodipeptide scaffold, followed by modifications by VftPT and VftAT.

## Abstract

Penicillium polonicum,
a common
spoilage fungus affecting stored grains, nuts, and dried fruits, produces
diverse secondary metabolites, including the indole-diketopiperazine
derivative verrucofortine. Here, we elucidate its biosynthetic pathway
through targeted gene deletion in a constructed low-metabolite-background
strain and biochemical characterization with recombinant proteins.
A nonribosomal peptide synthetase (VftPS) is responsible for assembling
the cyclodipeptide scaffold, which is then modified by the prenyltransferase
VftPT and the acetyltransferase VftAT. Notably, VftPT shows higher
catalytic efficiency toward all the tested tryptophan-containing cyclodipeptides
for C3ß-prenylation at the indole ring than
its known homologues, highlighting its potential for biocatalysis
and small molecule modification.