title: Alternative modular polyketide synthase expression controls macrolactone structure.
abstract: Modular polyketide synthases are giant multifunctional enzymes that catalyse the condensation of small carboxylic acids such as acetate and propionate into structurally diverse polyketides that possess a spectrum of biological activities. In a modular polyketide synthase, an enzymatic domain catalyses a specific reaction, and three to six enzymatic domains involved in a condensation-processing cycle are organized into a module. A fundamental aspect of a modular polyketide synthase is that its module arrangement linearly specifies the structure of its polyketide product. Here we report a natural example in which alternative expression of the pikromycin polyketide synthase results in the generation of two macrolactone structures. Expression of the full-length modular polyketide synthase PikAIV in Streptomyces venezuelae generates the 14-membered ring macrolactone narbonolide, whereas expression of the amino-terminal truncated form of PikAIV leads to 'skipping' of the final condensation cycle in polyketide biosynthesis to generate the 12-membered ring macrolactone 10-deoxymethynolide. Our findings provide insight into the structure and function of modular polyketide synthases, as well as a new set of tools to generate structural diversity in polyketide natural products.
authors.affiliation: Department of Microbiology and Biological Process Technology Institute, University of Minnesota, Minneapolis 55455, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xue
authors.forename: D H
authors.initials: DH
authors.lastname: Sherman
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism; D015153:Blotting, Western; D007783:Lactones / Q000737:chemistry*; D018942:Macrolides; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D007783:Lactones; D018942:Macrolides; D009097:Multienzyme Complexes; C008517:methymycin; C079477:10-deoxymethynolide; C003145:picromycin