Lanthipeptides are polycyclic peptides characterized bythe presence of lanthionine (Lan) and/or methyllanthionine (MeLan).They are members of the ribosomally synthesized and post-translation-ally modified peptides (RiPPs). The stereochemical configuration of(Me)Lan cross-links is important for the bioactivity of lanthipeptides. Todate, MeLan residues in characterized lanthipeptides have either the2S,3Sor 2R,3Rstereochemistry. Herein, we reconstituted inEscherichiacolithe biosynthetic pathway toward SapT, a class I lanthipeptide thatexhibits morphogenetic activity. Through the synthesis of standards, theheterologously produced peptide was shown to possess three MeLanresidues with the 2S,3Rstereochemistry (D-allo-L-MeLan), thefirst timesuch stereochemistry has been observed in a lanthipeptide. Bioinformaticanalysis of the biosynthetic enzymes suggests this stereochemistry may also be present in other lanthipeptides. Analysis of anothergene cluster inStreptomyces coelicolorthat is widespread in actinobacteria confirmed another example ofD-allo-L-MeLan and verifiedthe bioinformatic prediction. We propose a mechanism for the origin of the unexpected stereochemistry and provide support usingsite-directed mutagenesis.
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