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Crystal structure and mechanism of a bacterial fluorinating enzyme


Fluorine is the thirteenth most abundant element in the earth's crust, but fluoride concentrations in surface water are low and fluorinated metabolites are extremely rare1,2. The fluoride ion is a potent nucleophile in its desolvated state, but is tightly hydrated in water and effectively inert. Low availability and a lack of chemical reactivity have largely excluded fluoride from biochemistry: in particular, fluorine's high redox potential precludes the haloperoxidase-type mechanism3,4 used in the metabolic incorporation of chloride and bromide ions. But fluorinated chemicals are growing in industrial importance, with applications in pharmaceuticals, agrochemicals and materials products5,6,7. Reactive fluorination reagents requiring specialist process technologies are needed in industry and, although biological catalysts for these processes are highly sought after, only one enzyme that can convert fluoride to organic fluorine has been described8. Streptomyces cattleya can form carbon–fluorine bonds9 and must therefore have evolved an enzyme able to overcome the chemical challenges of using aqueous fluoride. Here we report the sequence and three-dimensional structure of the first native fluorination enzyme, 5′-fluoro-5′-deoxyadenosine synthase, from this organism. Both substrate and products have been observed bound to the enzyme, enabling us to propose a nucleophilic substitution mechanism for this biological fluorination reaction.

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Figure 1: 5′-FDAS from S. cattleya catalyses the formation of 5′-FDA from SAM and an F- ion.
Figure 2: Structure of 5′-FDAS, drawn by PyMOL31.
Figure 3: Fo–Fc electron density maps with phases calculated from models that do not include ligand.
Figure 4: Representation of 5′-FDA and methionine bound to the enzyme, showing hydrogen-bonding to the fluoromethyl group from Ser 158, and the anti relationship between the C–F bond (red) and the disconnected C–S bond (dotted red) of SAM that is indicative of an SN2 reaction course.


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We thank M. Dorward for technical assistance and G. Leonard for help with data collection. J.H.N. is a Biotechnology and Biological Sciences Research Council (BBSRC) Career Development Fellow; H.D. was supported by the BBSRC; D.O.H. thanks the BBSRC for financial support; J.H.N. thanks the Wellcome Trust.

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Correspondence to James H. Naismith.

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Dong, C., Huang, F., Deng, H. et al. Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature 427, 561–565 (2004).

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