Unexpected Methyllanthionine Stereochemistry in the Morphogenetic Lanthipeptide SapT

Raymond Sarksian, Julian D. Hegemann, Max A. Simon, Jeella Z. Acedo, Wilfred A. Van Der Donk

Research output: Contribution to journalArticlepeer-review


Lanthipeptides are polycyclic peptides characterized by the presence of lanthionine (Lan) and/or methyllanthionine (MeLan). They are members of the ribosomally synthesized and post-translationally modified peptides (RiPPs). The stereochemical configuration of (Me)Lan cross-links is important for the bioactivity of lanthipeptides. To date, MeLan residues in characterized lanthipeptides have either the 2S,3S or 2R,3R stereochemistry. Herein, we reconstituted in Escherichia coli the biosynthetic pathway toward SapT, a class I lanthipeptide that exhibits morphogenetic activity. Through the synthesis of standards, the heterologously produced peptide was shown to possess three MeLan residues with the 2S,3R stereochemistry (d-allo-l-MeLan), the first time such stereochemistry has been observed in a lanthipeptide. Bioinformatic analysis of the biosynthetic enzymes suggests this stereochemistry may also be present in other lanthipeptides. Analysis of another gene cluster in Streptomyces coelicolor that is widespread in actinobacteria confirmed another example of d-allo-l-MeLan and verified the bioinformatic prediction. We propose a mechanism for the origin of the unexpected stereochemistry and provide support using site-directed mutagenesis.

Original languageEnglish (US)
Pages (from-to)6373-6382
Number of pages10
JournalJournal of the American Chemical Society
Issue number14
StatePublished - Apr 13 2022

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry


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