Expanding the Fluorine Chemistry of Living Systems Using Engineered Polyketide Synthase Pathways

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Science  06 Sep 2013:
Vol. 341, Issue 6150, pp. 1089-1094
DOI: 10.1126/science.1242345

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Stitching in Fluoroacetate

Polyketide synthase enzymes stitch together an impressively diverse series of organic compounds from simple acetate and propionate building blocks. Walker et al. (p. 1089) now show that these biochemical pathways can be engineered to incorporate fluoroacetate—a primary product of the only known native enzymatic fluorination route—into tri- and tetraketides. In Escherichia coli cells, this process shows potential as a versatile means of inserting fluorine substituents into a range of complex molecules for use in pharmaceutical and agrochemical research.


Organofluorines represent a rapidly expanding proportion of molecules that are used in pharmaceuticals, diagnostics, agrochemicals, and materials. Despite the prevalence of fluorine in synthetic compounds, the known biological scope is limited to a single pathway that produces fluoroacetate. Here, we demonstrate that this pathway can be exploited as a source of fluorinated building blocks for introduction of fluorine into natural-product scaffolds. Specifically, we have constructed pathways involving two polyketide synthase systems, and we show that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. We further show that fluorine can be inserted site-selectively and introduced into polyketide products in vivo. These results highlight the prospects for the production of complex fluorinated natural products using synthetic biology.

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