Abstract
Posttranslational modification of amino acids confers a range of structural features and activities on ribosomally synthesized peptides, many of which have potent antimicrobial or other biological activities. Cypemycin is an extensively modified linear peptide produced by Streptomyces sp. OH-4156 with potent in vitro activity against mouse leukemia cells. Cypemycin does not contain lanthionine bridges but exhibits some of the structural features of lantibiotics, notably dehydrated threonines (dehydrobutyrines) and a C-terminal S-[(Z)-2-aminovinyl]-D-cysteine. Consequently it was classified as a member of the lantibiotic family of posttranslationally modified peptides. Cypemycin also possesses two L-allo-isoleucine residues and an N-terminal N,N-dimethylalanine, both unique amino acid modifications. We identified and heterologously expressed the cypemycin biosynthetic gene cluster and performed a mutational analysis of each individual gene. We show that even the previously described modifications are carried out by unusual enzymes or via a modification pathway unrelated to lantibiotic biosynthesis. Bioinformatic analysis revealed the widespread occurrence of cypemycin-like gene clusters within the bacterial kingdom and in the Archaea. Cypemycin is the founding member of an unusual class of posttranslationally modified ribosomally synthesized peptides, the linaridins.