title: Nostophycin biosynthesis is directed by a hybrid polyketide synthase-nonribosomal peptide synthetase in the toxic cyanobacterium Nostoc sp. strain 152.
abstract: Cyanobacteria are a rich source of natural products with interesting pharmaceutical properties. Here, we report the identification, sequencing, annotation, and biochemical analysis of the nostophycin (npn) biosynthetic gene cluster. The npn gene cluster spans 45.1 kb and consists of three open reading frames encoding a polyketide synthase, a mixed polyketide nonribosomal peptide synthetase, and a nonribosomal peptide synthetase. The genetic architecture and catalytic domain organization of the proteins are colinear in arrangement, with the putative order of the biosynthetic assembly of the cyclic heptapeptide. NpnB contains an embedded monooxygenase domain linking nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) catalytic domains and predicted here to hydroxylate the nostophycin during assembly. Expression of the adenylation domains and subsequent substrate specificity assays support the involvement of this cluster in nostophycin biosynthesis. Biochemical analyses suggest that the loading substrate of NpnA is likely to be a phenylpropanoic acid necessitating deletion of a carbon atom to explain the biosynthesis of nostophycin. Biosyntheses of nostophycin and microcystin resemble each other, but the phylogenetic analyses suggest that they are distantly related to one another.
authors.affiliation: Department of Food and Environmental Sciences, Division of Microbiology, P.O. Box 56, Viikki Biocenter, Viikinkaari 9, FIN-00014 University of Helsinki, Finland.
authors.forename: David P
authors.initials: DP
authors.lastname: Fewer
authors.forename: Julia
authors.initials: J
authors.lastname: Osterholm
authors.forename: Leo
authors.initials: L
authors.lastname: Rouhiainen
authors.forename: Jouni
authors.initials: J
authors.lastname: Jokela
authors.forename: Matti
authors.initials: M
authors.lastname: Wahlsten
authors.forename: Kaarina
authors.initials: K
authors.lastname: Sivonen
mesh_terms: D001427:Bacterial Toxins / Q000096:biosynthesis*; D053898:Biosynthetic Pathways / Q000235:genetics; D016000:Cluster Analysis; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D050939:Gene Fusion; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D005810:Multigene Family; D046937:Nostoc / Q000201:enzymology* / Q000378:metabolism*; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000096:biosynthesis*; D010802:Phylogeny; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D001427:Bacterial Toxins; D004269:DNA, Bacterial; D010456:Peptides, Cyclic; D048630:Polyketide Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase