Enzymatic fluorination and biotechnological development of the fluorinase

David O'Hagan (Corresponding Author), Hai Deng (Corresponding Author)

Research output: Contribution to journalArticle

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Abstract

Despite a long and distinguished history focused on the isolation and structural elucidation of secondary metabolites from all classes of organisms, organic chemists have only securely identified five unique fluorine-containing metabolites from an estimated 130 000 structurally characterized natural
products (see Figure 1). This absence of fluorometabolites in our natural product inventory arises for several reasons. Fluoride ion has very low abundance (F− = 1.3 ppm) in the oceans relative to chloride (Cl− = 20 000 ppm) and bromide
(Br− = 70 ppm), and thus its bioavailability is low. It also has the highest heat of hydration (∼120 kcal mol−1); therefore, to achieve nucleophilic catalysis from water, an enzyme has to evolve a desolvation strategy. Much of the biochemistry of the other halogens involves the oxidation of halide ions (X−) to halonium ions (X+) or halide radicals (X·), but the high electronegativity of fluorine mitigates against an oxidation approach. It is interesting that iodide, which is even less
abundant than fluoride in surface water (F− = 1.3 ppm vs I− = 0.02 ppm), has given rise to ∼120 iodine-containing natural products. This is because iodide, unlike fluoride, is readily oxidized by haloperoxidases, and it finds an entry into
enzymology through the relative ease of iodonium ion (I+) generation. The haloperoxidases do not oxidize F− because the oxidation potential of hydrogen peroxide (−1.8 eV) is above that of fluoride (F− = −2.87 eV) but lower than that of the other halogens (Cl− = −1.36 eV; Br− = −1.07 ev; I− = −0.54ev). Thus, the physical properties of fluoride appear to have limited the evolution of fluorine biochemistry. However, nature has found a way, and a few rare fluorometabolites have been identified, as illustrated in Figure 1. The most ubiquitious metabolite is fluoroacetate 1, which was first identified from
Dichapetalum cymosum in South Africa but has been subsequently found in a variety of plants across the globe, particularly in southern and tropical regions of Africa, Australia, and Brazil
Original languageEnglish
Pages (from-to)634-649
Number of pages16
JournalChemical Reviews
Volume115
Issue number2
Early online date25 Sep 2014
DOIs
Publication statusPublished - 28 Jan 2015

Fingerprint

Fluorination
Fluorides
Fluorine
Metabolites
Ions
Biochemistry
Halogens
Iodides
Biological Products
Oxidation
Fluoroacetates
Electronegativity
Bromides
Surface waters
Iodine
Hydration
Hydrogen Peroxide
Catalysis
Chlorides
Physical properties

Keywords

  • Enzymatic Fluorination
  • Biotechnological Developments

Cite this

Enzymatic fluorination and biotechnological development of the fluorinase. / O'Hagan, David (Corresponding Author); Deng, Hai (Corresponding Author).

In: Chemical Reviews, Vol. 115, No. 2, 28.01.2015, p. 634-649.

Research output: Contribution to journalArticle

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abstract = "Despite a long and distinguished history focused on the isolation and structural elucidation of secondary metabolites from all classes of organisms, organic chemists have only securely identified five unique fluorine-containing metabolites from an estimated 130 000 structurally characterized naturalproducts (see Figure 1). This absence of fluorometabolites in our natural product inventory arises for several reasons. Fluoride ion has very low abundance (F− = 1.3 ppm) in the oceans relative to chloride (Cl− = 20 000 ppm) and bromide(Br− = 70 ppm), and thus its bioavailability is low. It also has the highest heat of hydration (∼120 kcal mol−1); therefore, to achieve nucleophilic catalysis from water, an enzyme has to evolve a desolvation strategy. Much of the biochemistry of the other halogens involves the oxidation of halide ions (X−) to halonium ions (X+) or halide radicals (X·), but the high electronegativity of fluorine mitigates against an oxidation approach. It is interesting that iodide, which is even lessabundant than fluoride in surface water (F− = 1.3 ppm vs I− = 0.02 ppm), has given rise to ∼120 iodine-containing natural products. This is because iodide, unlike fluoride, is readily oxidized by haloperoxidases, and it finds an entry intoenzymology through the relative ease of iodonium ion (I+) generation. The haloperoxidases do not oxidize F− because the oxidation potential of hydrogen peroxide (−1.8 eV) is above that of fluoride (F− = −2.87 eV) but lower than that of the other halogens (Cl− = −1.36 eV; Br− = −1.07 ev; I− = −0.54ev). Thus, the physical properties of fluoride appear to have limited the evolution of fluorine biochemistry. However, nature has found a way, and a few rare fluorometabolites have been identified, as illustrated in Figure 1. The most ubiquitious metabolite is fluoroacetate 1, which was first identified fromDichapetalum cymosum in South Africa but has been subsequently found in a variety of plants across the globe, particularly in southern and tropical regions of Africa, Australia, and Brazil",
keywords = "Enzymatic Fluorination, Biotechnological Developments",
author = "David O'Hagan and Hai Deng",
note = "We thank all of our colleagues at the University of St. Andrews who worked on this project over the years, particularly Jim Naismith’s lab for structural biology support. It has been a pleasure to engage in fluorinase collaborations with many scientists in other laboratories including Walter Thiel and Hans Martin Senn of the Max Planck in Mulheim; Bradley Moore and Alessandra Eustaquio of the Scripps Institution of ́Ocenaography; Matteo Zanda, Sergio D’Allangelo, Lutz Schweiger, Juozas Domarkas, and Ian Fleming of the University of Aberdeen; Wim Versees, Jan Steyaert, and John N. Barlow of ́ Vrije Universiteit Brussel; Jan Passchier and Mayca Onega at Imanova in London; Xiang-Gu-Li of the University of Turku; Bert Windhorst and Danielle Vugts of the Free University, Amsterdam; Kwaku Kyeremeh of the University of Ghana; Yi Yu of Wuhan University; and Hong-Yu Oh of Jiaotong University. D.OH acknowledges the Royal Society for a Wolfson Research Merit Award.",
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N1 - We thank all of our colleagues at the University of St. Andrews who worked on this project over the years, particularly Jim Naismith’s lab for structural biology support. It has been a pleasure to engage in fluorinase collaborations with many scientists in other laboratories including Walter Thiel and Hans Martin Senn of the Max Planck in Mulheim; Bradley Moore and Alessandra Eustaquio of the Scripps Institution of ́Ocenaography; Matteo Zanda, Sergio D’Allangelo, Lutz Schweiger, Juozas Domarkas, and Ian Fleming of the University of Aberdeen; Wim Versees, Jan Steyaert, and John N. Barlow of ́ Vrije Universiteit Brussel; Jan Passchier and Mayca Onega at Imanova in London; Xiang-Gu-Li of the University of Turku; Bert Windhorst and Danielle Vugts of the Free University, Amsterdam; Kwaku Kyeremeh of the University of Ghana; Yi Yu of Wuhan University; and Hong-Yu Oh of Jiaotong University. D.OH acknowledges the Royal Society for a Wolfson Research Merit Award.

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