Global Genome Mining Reveals a Cytochrome P450-Catalyzed Cyclization of Crownlike Cyclodipeptides with Neuroprotective Activity
Jessie James Limlingan Malit, Wenchao Liu, Aifang Cheng, Subhasish Saha, Ling-Li Liu, Pei‐Yuan Qian
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.
Topics & Concepts
Heterologous expressionChemistryHeterologousGenomeNeuroprotectionCytochrome P450GeneBiosynthesisCytochromeComputational biologyBiochemistryStereochemistryEnzymeBiologyRecombinant DNAPharmacologyMicrobial Natural Products and BiosynthesisChemical Synthesis and AnalysisPeptidase Inhibition and Analysis