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

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 <i>Saccharopolyspora hirsuta</i> DSM 44795 led to the identification of two novel crownlike CDPs, cyctetryptomycin A (<b>4</b>) and B (<b>5</b>), 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.