UC Berkeley

Polyketide synthases (PKSs) are versatile multimodular enzymes that biosynthesize molecules in an assembly line fashion. The discrete and sequential processing of the polyketide intermediates by domains in PKSs give rise to our ability to retrobiosynthetically predict the structure of the polyketide produced by a PKS simply by analyzing the amino acid sequence of said PKS. Likewise, much work has been done to rationally engineer novel PKSs to make designer polyketides by using retrobiosynthetic logic to stitch together PKS domains in the order required to produce a desired molecule. In this work, we sought to understand the engineering principles required to construct functional chimeras of PKSs with various reductive loop swaps to produce polyketides with varying degrees of reduction in Streptomyces albus. Furthermore, we sought to make the advantageous heterologous host, Pseudomonas putida, well adapted to produce polyketides, particularly free fatty acid-derived polyketides, by eliminating free fatty acid catabolic pathways and demonstrating the production of medium-chain free fatty acids. Finally, we present ongoing efforts to produce free fatty acid-derived polyketides that can give rise to valuable flavorant delta-lactones.