(467d) Ribosomal Peptides Containing Fatty Acyl Moieties Synthesized By Noncannonical Kas III Enzymes

Lipopeptides constitute a large group of natural products with significant medical importance. While most of the representatives are produced by nonribosomal peptide synthetases (NRPSs), few lipopeptides were characterized with ribosomal origins. Here we report the discovery of ribosomally derived, N-acylated aminovinyl-cysteine-containing lipopeptides, hereafter termed as lipoavitides. Structural elucidation of lipoavitide A, the first member in this class obtained through heterologous expression, revealed its unique combination of nonproteinogenic residues including an aminovinyl-cysteine (AviCys), a β-hydroxy-N,N-dimethyl-L-histidine (hdmHis), a glycosylated tyrosine, a D-alanine, as well as an unprecedented N-terminal 4- hydroxy- 2, 4- dimethyl-pentanoyl (HDMP) moiety. Genes involved in synthesizing these nonproteinogenic residues were predicted by bioinformatics and confirmed by gene deletion study. Additionally, further characterization of the biosynthetic machinery implied that the HDMP moiety is formed by a multistep reaction process initiated by a noncanonical KAS III enzyme LipC. Overall, lipoavitides represent a new class of ribosomally derived lipopeptides, and its distinct biosynthetic machinery has significant potential to be adapted to the lipopeptide engineering for drug development.