P450-Modified Ribosomally Synthesized Peptides with Aromatic Cross-Links

Cyclization of linear peptides is an effective strategy
to convert flexible molecules into rigid compounds, which is of great
significance for enhancing the peptide stability and bioactivity.
Despite significant advances in the past few decades, Nature and chemists’
ability to macrocyclize linear peptides is still quite limited. P450
enzymes have been reported to catalyze macrocyclization of peptides
through cross-linkers between aromatic amino acids with only three
examples. Herein, we developed an efficient workflow for the identification
of P450-modified RiPPs in bacterial genomes, resulting in the discovery
of a large number of P450-modified RiPP gene clusters. Combined with
subsequent expression and structural characterization of the products,
we have identified 11 novel P450-modified RiPPs with different cross-linking
patterns from four distinct classes. Our results greatly expand the
structural diversity of P450-modified RiPPs and provide new insights
and enzymatic tools for the production of cyclic peptides.