A Topologically Distinct Modified Peptide with Multiple Bicyclic Core Motifs Expands the Diversity of Microviridin-Like Peptides.

Microviridins are ribosomally synthesized and post-translationally modified peptides (RiPPs) that contain multiple intramolecular ω-ester or ω-amide crosslinks between two side chains in peptides. This type of the side-to-side macrocyclization may generate diverse structures with distinct topology and ring sizes, but the majority of the microviridin-like RiPPs present only a single consensus sequence with a tricyclic architecture. Here, we expanded the natural diversity of the microviridin-like modified peptides by determining the crosslinking connectivity of a new modified peptide, mTgnA and its homologous RiPPs, which we named the thuringinin group. Members of the thuringinin group have core motifs with a distinct consensus sequence, which is transformed to a novel hairpin-like bicyclic structure by the cognate ATP-grasp enzyme. We suggest that the microviridin-like RiPPs naturally have novel sequences and architectures beyond those found in microviridins and comprise a larger RiPP family, termed omega-ester containing peptides (OEPs).
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