1. Department of Microbiology and Biological Process Technology Institute, University of Minnesota, Box 196, 1460 Mayo Memorial Building, Minneapolis, Minnesota 55455, USA

Correspondence to: David H. Sherman Correspondence and requests for materials should be addressed to D.H.S. (e-mail: Email: david-s@biosci.umn.edu).

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^{1, 2}. 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 module³. A fundamental aspect of a modular polyketide synthase is that its module arrangement linearly specifies the structure of its polyketide product³. 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.