Bacterial Cytochrome P450 Catalyzed Post‐translational Macrocyclization of Ribosomal Peptides**

• DOI: 10.1002/anie.202311533
• Publication Date: 2023-09-28T10:16:06Z
• Authors: Bei‐Bei He; Jing Liu; Zhuo Cheng; Runze Liu; Zheng Zhong; Ying Gao; Hongyan Liu; Zhi‐Man Song; Yongqi Tian; Yong‐Xin Li
• Keywords: Biological Products; Genome; Bacteria; Cytochrome P-450 Enzyme System; Peptides; Ribosomes; Protein Processing, Post-Translational

AbstractRibosomally synthesized and post‐translationally modified peptides (RiPPs) are a fascinating group of natural products that exhibit diverse structural features and bioactivities. P450‐catalyzed RiPPs stand out as a unique but underexplored family. Herein, we introduce a rule‐based genome mining strategy that harnesses the intrinsic biosynthetic principles of RiPPs, including the co‐occurrence and co‐conservation of precursors and P450s and interactions between them, successfully facilitating the identification of diverse P450‐catalyzed RiPPs. Intensive BGC characterization revealed four new P450s, KstB, ScnB, MciB, and SgrB, that can catalyze the formation of Trp‐Trp‐Tyr (one C−C and two C−N bonds), Tyr‐Trp (C−C bond), Trp‐Trp (C−N bond), and His‐His (ether bond) crosslinks, respectively, within three or four residues. KstB, ScnB, and MciB could accept non‐native precursors, suggesting they could be promising starting templates for bioengineering to construct macrocycles. Our study highlights the potential of P450s to expand the chemical diversity of strained macrocyclic peptides and the range of biocatalytic tools available for peptide macrocyclization.