Alternative modular polyketide synthase expression controls macrolactone structure

Modular polyketide synthases are giant multifunctional enzymes that catalys e the condensation of small carboxylic acids such as acetate and propionate into structurally diverse polyketides that possess a spectrum of biologica l activities(1,2). In a modular polyketide synthase, an enzymatic domain ca talyses a specific reaction, and three to six enzymatic domains involved in a condensation-processing cycle are organized into a module(3). A fundamen tal aspect of a modular polyketide synthase is that its module arrangement linearly specifies the structure of its polyketide product(3). Here we repo rt a natural example in which alternative expression of the pikromycin poly ketide synthase results in the generation of two macrolactone structures. E xpression of the full-length modular polyketide synthase PikAIV in Streptom yces venezuelae generates the 11-membered ring macrolactone narbonolide, wh ereas expression of the amino-terminal truncated form of PikAIV leads to 's kipping' of the final condensation cycle in polyketide biosynthesis to gene rate the 12-membered ring macrolactone 10-deoxymethynolide. Our findings pr ovide insight into the structure and function of modular polyketide synthas es, as well as a new set of tools to generate structural diversity in polyk etide natural products.