Diversity and Classification of the Actinopeptins: A New Family of Lanthipeptides Within the Genomes from the Phylum Actinomycetota

Background/Objectives: Lanthipeptides are post-translationally modified compounds and have broad industrial potential. Six distinct classes of lanthipeptides are defined by the biosynthetic enzymes that install lanthionine and β-methyl-lanthionine. Notably, class II lanthipeptides are modified by the LanM enzyme and are encoded by specific biosynthetic clusters found in both Gram-positive and Gram-negative bacteria. Among bacterial phyla, the Actinomycetota is particularly notable for encoding a rich diversity of lanthipeptides. In this study, we investigated the diversity of a new class II lanthipeptide group, the actinopeptin family, within the phylum Actinomycetota. Methods: Using genome-mining tools, we analyzed 85 producer genomes encoding actinopeptins. Results: When comparing clusters, we found that high overall similarity is restricted to only a few sequences, whereas most clusters display marked differences, which highlights the broad diversity of this lanthipeptide family. Our comparative analysis revealed that while the leader peptide is conserved across this group, core peptides are highly diverse. Conclusions: This finding allowed us to categorize the entire family into distinct groups. We also identified clusters encoding multiple peptides modified by LanM, suggesting that it may exhibit substrate promiscuity. This study highlights the actinopeptin family as a promising source of new compounds.