title: Spiroketal polyketide formation in Sorangium: identification and analysis of the biosynthetic gene cluster for the highly cytotoxic spirangienes.
abstract: Natural products constitute important lead structures in drug discovery. In bacteria, they are often synthesized by large, modular multienzyme complexes. Detailed analysis of the biosynthetic machinery should enable its directed engineering and production of desirable analogs. The myxobacterium Sorangium cellulosum So ce90 produces the cytotoxic spiroketal polyketide spirangien, for which we describe the identification and functional analysis of the biosynthetic pathway. The gene cluster spans 88 kb and encodes 7 type I polyketide synthases and additional enzymes such as a stand-alone thioesterase and 2 methyltransferases. Inactivation of two cytochrome P(450) monooxygenase genes resulted in the production of acyclic spirangien derivatives, providing direct evidence for the involvement of these enzymes in spiroketal formation. The presence of large DNA repeats is consistent with multiple rounds of gene duplication during the evolution of the biosynthetic gene locus.
authors.affiliation: Pharmaceutical Biotechnology, Saarland University, 66041 Saarbrücken, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Frank
authors.forename: Jens
authors.initials: J
authors.lastname: Knauber
authors.forename: Heinrich
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Maren
authors.initials: M
authors.lastname: Scharfe
authors.forename: Helmut
authors.initials: H
authors.lastname: Blöcker
authors.forename: Stefan
authors.initials: S
authors.lastname: Beyer
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000080:Acetals / Q000737:chemistry / Q000378:metabolism; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism; D005798:Genes, Bacterial; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D005810:Multigene Family; D016297:Mutagenesis, Site-Directed; D009231:Myxococcales / Q000235:genetics* / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000080:Acetals; D004269:DNA, Bacterial; D005231:Fatty Acids, Unsaturated; D018942:Macrolides; C523683:spirangien A; D048630:Polyketide Synthases