Unique post-translational oxime formation in the biosynthesis of the azolemycin complex of novel ribosomal peptides from Streptomyces sp. FXJ1.264

• Published in: Chemical science (Cambridge) Vol. 7; no. 1; pp. 482 - 488
• Main Authors: Liu, Ning, Song, Lijiang, Liu, Minghao, Shang, Fei, Anderson, Zoe, Fox, David J, Challis, Gregory L, Huang, Ying
• Format: Journal Article
• Language: English
• Published: England 01.01.2016
• Subjects: Biosynthesis; Clusters; Derivatives; Formations; Genes; Oximes; Peptides; Precursors; Streptomyces; Streptomycetes
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c5sc03021h

Streptomycetes are a rich source of bioactive specialized metabolites, including several examples of the rapidly growing class of ribosomally-biosynthesized and post-translationally-modified peptide (RiPP) natural products. Here we report the discovery from sp. FXJ1.264 of azolemycins A-D, a complex of novel linear azole-containing peptides incorporating a unique oxime functional group. Bioinformatics analysis of the sp. FXJ1.264 draft genome sequence identified a cluster of genes that was hypothesized to be responsible for elaboration of the azolemycins from a ribosomally-biosynthesized precursor. Inactivation of genes within this cluster abolished azolemycin production, consistent with this hypothesis. Moreover, mutants lacking the and genes accumulated azolemycin derivatives lacking the -methyl groups and an amino group in place of the N-terminal oxime (as well as proteolysed derivatives), respectively. Thus AzmE, a putative -adenosyl methionine-dependent methyl transferase, is responsible for late-stage -methylation reactions in azolemycin biosynthesis and AzmF, a putative flavin-dependent monooxygenase, catalyzes oxidation of the N-terminal amino group in an azolemycin precursor to the corresponding oxime. To the best of our knowledge, oxime formation is a hitherto unknown posttranslational modification in RiPP biosynthesis.