title: Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways.
abstract: 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-1460, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Walker
authors.forename: B W
authors.initials: BW
authors.lastname: Thuronyi
authors.forename: Louise K
authors.initials: LK
authors.lastname: Charkoudian
authors.forename: Brian
authors.initials: B
authors.lastname: Lowry
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.forename: Michelle C Y
authors.initials: MC
authors.lastname: Chang
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism*; D019117:Burkholderia / Q000201:enzymology; D003066:Coenzyme A Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli; D005463:Fluoroacetates / Q000737:chemistry / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008969:Molecular Sequence Data; D048630:Polyketide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D061065:Polyketides / Q000737:chemistry / Q000378:metabolism*; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D048372:Streptomyces coelicolor / Q000201:enzymology
chemical_list: D001426:Bacterial Proteins; D001688:Biological Products; D005463:Fluoroacetates; D061065:Polyketides; D048630:Polyketide Synthases; D003066:Coenzyme A Ligases; C550924:acetoacetyl-CoA synthase, Streptomyces