Expanding Catalytic Versatility of Modular Polyketide Synthases for Alcohol Biosynthesis

Abstract Modular polyketide synthases biosynthesize structurally diverse natural products by a set of catalytic domains that operate in an assembly line fashion. Although extensive research has focused on the rational reprogramming of modular polyketide synthases, little has been attempted to introduce uncanonical catalytic reactions on the assembly line. Here, we demonstrate the insertion of a thioester reductase domain, which can generate a terminal alcohol group instead of the canonical carboxylic acid, onto the assembly line polyketide synthases. We show that the didomain insertion of the acyl carrier protein and thioester reductase pair is generally effective for engineering of various polyketide synthase pathways. As a proof-of-concept, stereoselective and stereodivergent bioproduction of non-natural diols, namely 1,3-butanediols and 2-methyl-1,3-butanediols was achieved by harnessing the modularity of polyketide synthases. Our study expands the catalytic versatility of modular polyketide synthases and paves the way towards biosynthesis of designer alcohols.