Production of structurally diverse ketones by engineered polyketide synthases

Type I modular polyketide synthases (PKSs) are multi-domain megaenzymes that catalyze a programmed, step-wise chain extension reactions to produce structurally diverse polyketide intermediates attached onto the enzymes. Because different chain-release reactions could further diversify product structures, understanding the mechanisms are of considerable interest. Although type I modular PKSs can release their products in several different ways, none has been uncovered that releases its product as a ketone in nature. Here, we report engineered biosynthesis of structurally diverse b-keto-carboxylic acids by PKSs in vitro, which are then decarboxylated to produce the corresponding ketones. Some of the compounds are  industrially important solvents that heretofore have not been biologically produced. We also report ketone production in Escherichia coli. This methodology could allow us to produce a variety of ketones in microbes in a sustainable manner.