Linking Chemistry and Genetics in the Growing Cyanobactin Natural Products Family

SummaryRibosomal peptide natural products are ubiquitous, yet relatively few tools exist to predict structures and clone new pathways. Cyanobactin ribosomal peptides are found in ∼30% of all cyanobacteria, but the connection between gene sequence and structure was not defined, limiting the rapid identification of new compounds and pathways. Here, we report discovery of four orphan cyanobactin gene clusters by genome mining and an additional pathway by targeted cloning, which represented a tyrosine O-prenylating biosynthetic pathway. Genome mining enabled discovery of five cyanobactins, including peptide natural products from Spirulina supplements. A phylogenetic model defined four cyanobactin genotypes, which explain the synthesis of multiple cyanobactin structural classes and help direct pathway cloning and structure prediction efforts. These strategies were applied to DNA isolated from a mixed cyanobacterial bloom containing cyanobactins.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (403 K)Download as PowerPoint slideHighlights► A tyrosine-prenylating gene cluster and a previously uncharacterized compound were found ► Cyanobactin natural products were identified in Spirulina health food supplements ► Cyanobactin chemical structure-gene sequence relationships were defined ► These relationships enabled gene cloning from complex environmental samples