title: Genome Mining of Streptomyces sp. Tü 6176: Characterization of the Nataxazole Biosynthesis Pathway.
abstract: Streptomyces sp. Tü 6176 produces the cytotoxic benzoxazole nataxazole. Bioinformatic analysis of the genome of this organism predicts the presence of 38 putative secondary-metabolite biosynthesis gene clusters, including those involved in the biosynthesis of AJI9561 and its derivative nataxazole, the antibiotic hygromycin B, and ionophores enterobactin and coelibactin. The nataxazole biosynthesis gene cluster was identified and characterized: it lacks the O-methyltransferase gene required to convert AJI9561 into nataxazole. This O-methyltransferase activity might act as a resistance mechanism, as AJI9561 shows antibiotic activity whereas nataxazole is inactive. Moreover, heterologous expression of the nataxazole biosynthesis gene cluster in S. lividans JT46 resulted in the production of AJI9561. Nataxazole biosynthesis requires the shikimate pathway to generate 3-hydroxyanthranilate and an iterative type I PKS to generate 6-methylsalicylate. Production of nataxazole was improved up to fourfold by disrupting one regulatory gene in the cluster. An additional benzoxazole, 5-hydroxynataxazole is produced by Streptomyces sp. Tü 6176. 5-Hydroxynataxazole derives from nataxazole by the activity of an as yet unidentified oxygenase; this implies cross-talk between the nataxazole biosynthesis pathway and an unknown pathway.
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, C/ Julian Clavería S/N, 33006 Oviedo (Spain).
authors.forename: Carolina
authors.initials: C
authors.lastname: Cano-Prieto
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, C/ Julian Clavería S/N, 33006 Oviedo (Spain).
authors.forename: Raúl
authors.initials: R
authors.lastname: García-Salcedo
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, C/ Julian Clavería S/N, 33006 Oviedo (Spain).
authors.forename: Marina
authors.initials: M
authors.lastname: Sánchez-Hidalgo
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, C/ Julian Clavería S/N, 33006 Oviedo (Spain).
authors.forename: Alfredo F
authors.initials: AF
authors.lastname: Braña
authors.affiliation: Mikrobiologisches Institut, Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen (Germany).
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fiedler
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, C/ Julian Clavería S/N, 33006 Oviedo (Spain).
authors.forename: Carmen
authors.initials: C
authors.lastname: Méndez
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, C/ Julian Clavería S/N, 33006 Oviedo (Spain).
authors.forename: José A
authors.initials: JA
authors.lastname: Salas
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, C/ Julian Clavería S/N, 33006 Oviedo (Spain). olanocarlos@uniovi.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Olano
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D001583:Benzoxazoles / Q000378:metabolism* / Q000494:pharmacology; D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D006801:Humans; D051379:Mice; D005810:Multigene Family; D041681:NIH 3T3 Cells; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism
chemical_list: C423665:AJI 9561; D000900:Anti-Bacterial Agents; D001583:Benzoxazoles; C540755:nataxazole
keywords: AJI9561; benzoxazole; biosynthesis; genome mining; iterative type I PKS; natural products