Hyalucidin A: A Bacterial RiPP Featuring a Benzofuranoindoline Motif Biosynthesized by Tandem P450 Catalysis
Abstract
Abstract Despite the emergence of P450‐modified ribosomally synthesized and post‐translationally modified peptides (RiPPs) as a distinct and rapidly expanding class of natural products, their structural diversity has been limited to scaffolds catalyzed solely by single P450 enzymes. To access greater structural complexity, we targeted unexplored biosynthetic gene clusters encoding two P450s. This effort led to the discovery of hyalucidin A, which features the most intricate polycyclic cross‐linked architecture among reported P450‐RiPPs and represents the first bacterial RiPP containing a benzofuranoindoline motif. Through stepwise enzymatic analysis, combinatorial biosynthesis, and precursor peptide engineering, we deciphered the cooperative function and substrate tolerance of both P450s. Our work expands the biosynthetic logic of P450‐driven cyclization and provides a platform for engineering complex macrocyclic peptides.
Article Details
Authors (8)
Fang Zhou Yin
State Key Laboratory of Pharmaceutical Biotechnology Institute of Functional Biomolecules Department of Neurology Nanjing Drum Tower Hospital Chemistry and Biomedicine Innovation Center (ChemBIC) School of Life Sciences Nanjing University Nanjing 210023 China
Zi Jie Wang
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Nanjing Drum Tower Hospital, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences
Yi Ling Hu
State Key Laboratory of Pharmaceutical Biotechnology Institute of Functional Biomolecules Department of Neurology Nanjing Drum Tower Hospital Chemistry and Biomedicine Innovation Center (ChemBIC) School of Life Sciences Nanjing University Nanjing 210023 China
Cheng Li Liu
State Key Laboratory of Pharmaceutical Biotechnology Institute of Functional Biomolecules Department of Neurology Nanjing Drum Tower Hospital Chemistry and Biomedicine Innovation Center (ChemBIC) School of Life Sciences Nanjing University Nanjing 210023 China
Zhi Kai Guo
Hainan Key Laboratory of Tropical Microbe Resources Institute of Tropical Bioscience and Biotechnology Chinese Academy of Tropical Agricultural Sciences Haikou 571101 China
Ren Xiang Tan
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Nanjing Drum Tower Hospital, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences
Jing Shi
Hui Ming Ge
State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Nanjing Drum Tower Hospital, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences