Crystal structure and mechanism of a bacterial fluorinating enzyme

Changjiang Dong, Fanglu Hang, Hai Deng, Christoph Schaffrath, Jonathan B Spencer, David O'hagan, James H. Naismith (Corresponding Author)

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

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 rare. 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 mechanism 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 products. 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 described. Streptomyces cattleya can form carbon-fluorine bonds 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.

Original languageEnglish
Pages (from-to)561-565
Number of pages5
JournalNature
Volume427
Issue number6974
DOIs
Publication statusPublished - 5 Feb 2004

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Fluorides
Fluorine
Halogenation
Enzymes
Ions
Agrochemicals
Biological Phenomena
Water
Streptomyces
Bromides
Biochemistry
Oxidation-Reduction
Chlorides
Industry
Carbon
Technology
Pharmaceutical Preparations

Cite this

Dong, C., Hang, F., Deng, H., Schaffrath, C., Spencer, J. B., O'hagan, D., & Naismith, J. H. (2004). Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature, 427(6974), 561-565. https://doi.org/10.1038/nature02280

Crystal structure and mechanism of a bacterial fluorinating enzyme. / Dong, Changjiang; Hang, Fanglu; Deng, Hai; Schaffrath, Christoph ; Spencer, Jonathan B; O'hagan, David; Naismith, James H. (Corresponding Author).

In: Nature, Vol. 427, No. 6974, 05.02.2004, p. 561-565.

Research output: Contribution to journalArticle

Dong, C, Hang, F, Deng, H, Schaffrath, C, Spencer, JB, O'hagan, D & Naismith, JH 2004, 'Crystal structure and mechanism of a bacterial fluorinating enzyme', Nature, vol. 427, no. 6974, pp. 561-565. https://doi.org/10.1038/nature02280
Dong C, Hang F, Deng H, Schaffrath C, Spencer JB, O'hagan D et al. Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature. 2004 Feb 5;427(6974):561-565. https://doi.org/10.1038/nature02280
Dong, Changjiang ; Hang, Fanglu ; Deng, Hai ; Schaffrath, Christoph ; Spencer, Jonathan B ; O'hagan, David ; Naismith, James H. / Crystal structure and mechanism of a bacterial fluorinating enzyme. In: Nature. 2004 ; Vol. 427, No. 6974. pp. 561-565.
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AB - 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 rare. 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 mechanism 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 products. 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 described. Streptomyces cattleya can form carbon-fluorine bonds 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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