Enzyme-catalyzed C–F bond formation and cleavage

Wei, Tong; Huang, Qi; Li, Min; Wang, Jianbo

doi:10.1186/s40643-019-0280-6

Cited by 18 publications

(12 citation statements)

References 73 publications

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“…Therefore, the C–F bond cleavage requires a different mechanism than the C–H bond cleavage. The ability to cleave a C–F bond by TyrH has garnered significant interest and attention; − however, the molecular rationale for dual reactivity and catalytic intermediates remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Molecular Rationale for Partitioning between C–H and C–F Bond Activation in Heme-Dependent Tyrosine Hydroxylase

et al. 2021

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The heme-dependent L-tyrosine hydroxylases (TyrHs) in natural product biosynthesis constitute a new enzyme family in contrast to the nonheme iron enzymes for DOPA production. A representative TyrH exhibits dual reactivity of C-H and C-F bond cleavage when challenged with 3-fluoro-L-tyrosine (3-FTyr) as a substrate. However, little is known about how the enzyme mediates two distinct reactions. Herein, a new TyrH from the thermophilic bacterium Streptomyces sclerotialus (SsTyrH) was functionally and structurally characterized. A de novo crystal structure of the enzyme-substrate complex at 1.89-Å resolution provides the first comprehensive structural study of this hydroxylase. The binding conformation of L-tyrosine indicates that C-H bond hydroxylation is initiated by electron transfer. Mutagenesis studies confirmed that an active site histidine, His88, participates in catalysis. We also obtained a 1.68-Å resolution crystal structure in complex with the monofluorinated substrate, 3-F-Tyr, which shows one binding conformation but two orientations of the fluorine atom with a ratio of 7:3, revealing that the primary factor of product distribution is the substrate orientation. During in crystallo reaction, a ferric-hydroperoxo intermediate (compound 0, Fe 3+ -OOH) was observed with 3-F-Tyr as a substrate based on characteristic spectroscopic features. We determined the crystal structure of

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Section: Introductionmentioning

confidence: 99%

Molecular Rationale for Partitioning between C–H and C–F Bond Activation in Heme-Dependent Tyrosine Hydroxylase

et al. 2021

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“…Due to the small radius and high electronegativity, fluorine atoms can substitute hydrogen atoms with little impact on steric clash but great improvement on drug potency. − Fluorochemicals with unique physical, chemical, and biological properties including strong water or oil repellency and high chemical inertness and wear resistance , have been widely used in various fields. For instance, more than 20% of pharmaceuticals and 30% of agrochemicals are fluorochemicals. − Despite wide applications and valuable functions, they cause great environmental concerns due to their toxicity, persistence, and bioaccumulation, − which originate from the super inert C–F bond with an extremely high dissociation energy as large as 130 kcal mol –1 .…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Understanding of Fluoroacetate Dehalogenase-Catalyzed Degradation of Fluorocarboxylic Acids: A QM/MM Approach

Yue

Fan

Xin

et al. 2021

Environ. Sci. Technol.

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Fluorochemicals are persistent, bioaccumulative, and toxic compounds that are widely tributed in the environment. Developing efficient biodegradation strategies to decompose the fluorochemicals via breaking the inert C−F bonds presents a holistic challenge. As a promising biodegradation enzyme candidate, fluoroacetate dehalogenase (FAcD) has been reported as the only non-metallic enzyme to catalyze the cleavage of the strong C−F bond. Here, we systematically investigated the catalytic actions of FAcD toward its natural substrate fluoroacetate using molecular dynamics simulations and quantum mechanism/molecular mechanism calculations. We propose that the enzymatic transformation involves four elementary steps, (I) C−F bond activation, (II) nucleophilic attack, (III) C−O bond cleavage, and (IV) proton transfer. Our results show that nucleophilic attack is the rate-determining step. However, for difluoroacetate and trifluoroacetate, C−F bond activation, instead of nucleophilic attack, becomes the rate-determining step. We show that FAcD, originally recognized as α-fluorocarboxylic acid degradation enzyme, can catalyze the defluorination of difluoroacetate to glyoxylate, which is captured by our high-resolution mass spectrometry experiments. In addition, we employed amino acid electrostatic analysis method to screen potential mutation hotspots for tuning FAcD's electrostatic environment to favor substrate conversion. The comprehensive understanding of catalytic mechanism will inform a rational enzyme engineering strategy to degrade fluorochemicals for benefits of environmental sustainability.

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“…In nature, organohalogen compounds are mainly produced by haloperoxidases, a family of enzymes in which the existence of fluoroperoxidase members remains hitherto unknown [25]. In fact, the biosynthetic origin of the vast majority of naturally occurring organofluorinated molecules remains a mystery, and there is only one single example of the bioenzymatic formation of C-F bonds in nature [26]. It involves the fluorination of S-adenosyl-L-methionine (SAM) in Streptomyces cattleya by a natural fluorinase enzyme to 5 -fluoro-5 -deoxyadenosine (FDA) [27], which is further enzymatically converted to fluoroacetate (Scheme 1c)-a toxin for mammals.…”

Section: Introductionmentioning

confidence: 99%

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

2022

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Nucleophilic ionic sources of fluoride are essential reagents in the synthetic toolbox to access high added-value fluorinated building blocks unattainable by other means. In this review, we provide a concise description and rationale of the outstanding features of one of these reagents, tetramethylammonium fluoride (TMAF), as well as disclosing the different methods for its preparation, and how its physicochemical properties and solvation effects in different solvents are intimately associated with its reactivity. Furthermore, herein we also comprehensively describe its historic and recent utilization, up to December 2021, in C-F bond-forming reactions with special emphasis on nucleophilic aromatic substitution fluorinations with a potential sustainable application in industrial settings, as well as its use as a base capable of rendering unprecedented transformations.

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Enzyme-catalyzed C–F bond formation and cleavage

Cited by 18 publications

References 73 publications

Molecular Rationale for Partitioning between C–H and C–F Bond Activation in Heme-Dependent Tyrosine Hydroxylase

Molecular Rationale for Partitioning between C–H and C–F Bond Activation in Heme-Dependent Tyrosine Hydroxylase

Comprehensive Understanding of Fluoroacetate Dehalogenase-Catalyzed Degradation of Fluorocarboxylic Acids: A QM/MM Approach

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

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