Identification of Fluorinases from Streptomyces sp MA37, Norcardia brasiliensis, and Actinoplanes sp N902‐109 by Genome Mining

Deng, Hai; Ma, Long; Bandaranayaka, Nouchali; Qin, Zhiwei; Mann, Greg; Kyeremeh, Kwaku; Yu, Yi; Shepherd, Thomas; Naismith, James H.; O’Hagan, David

doi:10.1002/cbic.201300732

Cited by 102 publications

(92 citation statements)

References 19 publications

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“…N902-109. 296 FlA catalyzes a S N 2-type displacement reaction in which fluoride attacks the electrophilic C-5′ carbon of SAM to generate 5′- fl uoro-5′- d eoxy a denosine (5′-FlDA) with concomitant displacement of L-methionine. 297 …”

Section: S-adenosyl-l-methionine-dependent Halogenasesmentioning

confidence: 99%

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

et al. 2017

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Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C-H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally, albeit rarely, in metabolic pathways. This review details the scope and mechanism of nature’s halogenation and dehalogenation enzymatic strategies, highlights gaps in our understanding, and posits where new advances in the field might arise in the near future.

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Section: S-adenosyl-l-methionine-dependent Halogenasesmentioning

confidence: 99%

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

et al. 2017

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“…Following discovery of the first fluorinase, an in silico genome mining effort was conducted to identify four additional enzymes within this family. 61,62 …”

Section: Fluorination Biocatalystsmentioning

confidence: 99%

Halogenase engineering and its utility in medicinal chemistry

Fraley

Sherman

2018

Bioorganic & Medicinal Chemistry Letters

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Halogenation is commonly used in medicinal chemistry to improve the potency of pharmaceutical leads. While synthetic methods for halogenation present selectivity and reactivity challenges, halogenases have evolved over time to perform selective reactions under benign conditions. The optimization of halogenation biocatalysts has utilized enzyme evolution and structure-based engineering alongside biotransformation in a variety of systems to generate stable site-selective variants. The recent improvements in halogenase-catalyzed reactions has demonstrated the utility of these biocatalysts for industrial purposes, and their ability to achieve a broad substrate scope implies a synthetic tractability with increasing relevance in medicinal chemistry.

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“…The fluorinase enzyme, isolated originally from the soil bacterium Streptomyces cattleya 1 and recently identified in additional bacterial species, 2 catalyses formation of a C-F bond from fluoride ion and S-adenosylmethionine 1 (SAM), generating 5'-fluoro-5'-deoxyadenosine 2 (FDA) (Scheme 1). The reaction has been shown to proceed by an inversion of configuration, 3,4 and QM/MM calculations provide strong support for an S N 2 reaction mechanism.…”

Section: Introductionmentioning

confidence: 99%

Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme

Thompson

McMahon

Naismith

et al. 2016

Bioorganic Chemistry

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Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme, Bioorganic Chemistry (2015), doi: http:// dx.doi.org/10.1016/j.bioorg. 2015.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5',5'-Difluoro-5'-deoxyadenosine 7 (F 2 DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5'-fluoro-5'-deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F 2 DA 7 was found, however, not to undergo the enzyme catalysed reaction with L-selenomethionine, unlike FDA 2, which undergoes reaction with L-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F 2 DA 7 and tartrate was solved to 1.8 Å, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of fluoride for reaction. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed.

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Identification of Fluorinases from Streptomyces sp MA37, Norcardia brasiliensis, and Actinoplanes sp N902‐109 by Genome Mining

Cited by 102 publications

References 19 publications

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

Halogenase engineering and its utility in medicinal chemistry

Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme

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