Elucidating the mechanism of fluorinated extender unit loading for improved production of fluorine-containing polyketides

Significance

Polyketide natural products represent a rich source for discovery of new bioactive compounds. However, the optimization of polyketide structure for medicinal purposes can be difficult using chemical methods given their complexity. Site-selective introduction of fluorine into polyketides and other natural products is a particularly interesting area of exploration given the demonstrated effectiveness of fluorine in modulating the behavior of small-molecule therapeutics. Here, we show that fluorine can be inserted site-selectively by an engineered polyketide synthase system via a fluorinated monomer that becomes covalently tethered to the enzyme to complete a canonical reaction cycle. By increasing the throughput of fluorinated extender units, we can produce multiply fluorinated polyketide products by chemoenzymatic synthesis and target the production of complex structures.