Global Genome Mining Reveals a Cytochrome P450-Catalyzed Cyclization of Crownlike Cyclodipeptides with Neuroprotective Activity

Org Lett. 2021 Sep 3;23(17):6601-6605. doi: 10.1021/acs.orglett.1c01022. Epub 2021 Apr 8.

Abstract

We conducted global genome mining of 162,672 bacterial genomes and identified 829 cyclodipeptide (CDP) biosynthesis gene clusters (BGC) containing a cytochrome P450 gene. Heterologous expression of BGC from Saccharopolyspora hirsuta DSM 44795 led to the identification of two novel crownlike CDPs, cyctetryptomycin A (4) and B (5), which possess unprecedented complex macrocycle and show neuroprotective activity. The two cytochrome P450s found in the BGC catalyze sequential reactions leading to the cyclization of diketopiperazine dimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Cyclization
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / metabolism*
  • Diketopiperazines / chemistry
  • Diketopiperazines / metabolism*
  • Genome, Bacterial
  • Molecular Structure
  • Oxidation-Reduction
  • Peptides, Cyclic / biosynthesis*
  • Saccharopolyspora / chemistry*

Substances

  • Diketopiperazines
  • Peptides, Cyclic
  • Cytochrome P-450 Enzyme System

Supplementary concepts

  • Saccharopolyspora hirsuta