title: Freedom and constraint in engineered noncolinear polyketide assembly lines.
abstract: Many pharmacologically important natural products are assembled by modular type I polyketide synthases (PKS), which typically act in a unidirectional fashion. The synthases producing the unusual nitro-substituted polyketides neoaureothin (nor, also called spectinabilin) and aureothin (aur) are exceptional, as they employ individual modules iteratively. Here, we investigate the plasticity of the nor PKS and the factors governing the number of elongations catalyzed by the noncanonical module. Surprisingly, we observe that the nor PKS can mediate an additional chain elongation to yield the higher homolog homoneoaureothin. Furthermore, we design several truncated variants of the nor PKS to use them in the context of artificial assembly lines for aureothin and homoaureothin. The resulting polypropionate derivatives provide valuable insights into chain length control and reveal structure-activity relationships relating to the size of the polypropionate backbones. Overall, we show that iterative modules are remarkably adaptable while downstream modules are gatekeepers that select for correct polyketide chain length.
authors: Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.
authors: Yuki
authors: Y
authors: Sugimoto
authors: Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.
authors: Keishi
authors: K
authors: Ishida
authors: Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.
authors: Nelly
authors: N
authors: Traitcheva
authors: Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.
authors: Benjamin
authors: B
authors: Busch
authors: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany.
authors: Hans-Martin
authors: HM
authors: Dahse
authors: Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstr. 11a, 07745 Jena, Germany; Natural Product Chemistry, Friedrich Schiller University, Jena, Germany. Electronic address: christian.hertweck@hki-jena.de.
authors: Christian
authors: C
authors: Hertweck
mesh_terms: D001412:Bacillus subtilis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002867:Chromones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D013058:Mass Spectrometry; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009154:Mutation; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*; D011753:Pyrones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013302:Streptomyces / Q000201:enzymology / Q000378:metabolism
chemical_list: D002867:Chromones; D011753:Pyrones; C508401:spectinabilin; D048630:Polyketide Synthases; C012198:aureothin