Hoffmann_2003_Gene_311_171

The cloning, sequencing, annotation and biochemical analysis of the nostopeptolide (nos) biosynthetic gene cluster from the terrestrial cyanobacterium Nostoc sp. GSV224 is described. Nostopeptolides A1 and A2 are cyclic peptide-polyketide hybrid natural products possessing nine amino acid residues, a butyric acid group, and an internal acetate-derived unit that are linked by peptide and ester bonds. The nos gene cluster includes eight ORFs encompassing 40 kb and includes most of the genes predicted to be involved in the biosynthesis and transport of this group of nonapeptolides. The genetic architecture and domain organization of the nos synthetase, a mixed non-ribosomal peptide synthetase-polyketide synthase, is co-linear in arrangement with respect to the putative order of the biosynthetic assembly of the lipopeptolide. Biochemical analysis of the NosA1, NosC1 and NosD1 adenylation domains coupled with the recent characterization of the nosE and nosF gene products, which are involved in the biosynthesis of the rare non-proteinogenic amino acid residue L-4-methylproline from L-leucine, support the involvement of this gene cluster in nostopeptolide biosynthesis.