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

Wang, Yifan; Davis, Ian; Shin, Inchul; Xu, Hui; Liu, Aimin

doi:10.1021/jacs.1c00175

Cited by 19 publications

(61 citation statements)

References 70 publications

(163 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent work on a representative member of this family has provided a rationale for the partitioning between the two reactions in 3-F-Tyr. [19] A crystal structure of the enzyme with 3-F-Tyr shows that the substrate adopts a binding conformation with two orientations of the fluorine atom with a ratio of 7 : 3. The two orientations account for two different reaction paths.…”

Section: Histidine-ligated Hemesmentioning

confidence: 99%

Oxidative C−F Cleavage in Metalloenzymes and Model Compounds

Costas

Company

2021

Eur J Inorg Chem

View full text Add to dashboard Cite

Replacement of C−H by C−F bonds provides lipophilicity and chemical stability to organic molecules. These properties make organofluorides interesting compounds in agrochemistry, medicinal chemistry and also in materials. However, the same properties hamper their chemical degradation, resulting in an increasingly concerning environmental persistence, which is fueling the quest for biological and chemical reagents that could cleave the C−F bonds. The first part of this review makes an overview of oxidative enzymes known to defluorinate organic molecules. The second part reviews coordination complexes, originally designed as functional models of oxidative enzymes, that can also engage in related defluorination reactions. The manuscript is hoped to provide ideas for the development of novel catalytic methodologies.

show abstract

Section: Histidine-ligated Hemesmentioning

confidence: 99%

Oxidative C−F Cleavage in Metalloenzymes and Model Compounds

Costas

Company

2021

Eur J Inorg Chem

View full text Add to dashboard Cite

show abstract

“…[8][9][10] Recently, a new heme-based biocatalyst, Tyrosine Hydroxylase (TyrH), has been reported to selectively activate both C(sp 2 )−H and C-F bonds under mild reaction conditions. 11 In contrast to traditional CYP450 enzymes where a cysteine residue is ligated at the proximal position of heme, the TyrH enzyme is a histidine ligated heme-dependent tyrosine hydrolase that uses hydrogen peroxide for the C-H activation. TyrH catalyzes the oxidation of Tyr to produce L-3,4-dihydroxyphenylalanine (DOPA) using L-tyrosine (Tyr) as a native substrate.…”

Section: Introductionmentioning

confidence: 99%

“…TyrH catalyzes the oxidation of Tyr to produce L-3,4-dihydroxyphenylalanine (DOPA) using L-tyrosine (Tyr) as a native substrate. 11 However, in the presence of the 3-fluoro-L-tyrosine (3-F-Tyr) as a substrate, it oxidizes 3-F-Tyr to 3fluoro-5-hydroxy-L-tyrosine and DOPA in 1.4:1 as shown in Scheme 1. Very recently, the Xray structure of TyrH in complex with the Tyr and 3-F-Tyr was elucidated 11 , which shows two identical binding conformations of the native and 3-F-Tyr substrates in the active site of TyrH.…”

Section: Introductionmentioning

confidence: 99%

“…Another interesting feature revealed by the X-ray structure is the out-of-plane conformation of one of the propionate side chains. 11 The out-of-plane propionate is involved in hydrogen bonds with the side chain of S157 and S209 protein residues. The out-of-plane conformation is different from the other hemedependent enzymes, where both the propionate side chains exhibit in-plane conformation relative to the heme group.…”

Section: Introductionmentioning

confidence: 99%

“…The EPR study and the theoretical investigations confirm that the binding of the substrate in the active site results in the displacement of the aqua ligand and the production of pentacoordinate high spin Fe(III) species (S2). 11 The vacant site is then occupied by molecular hydrogen peroxide, which deprotonates to form a ferric-hydroperoxo intermediate also known as Cpd 0 (S3). From a mechanistic point of view, it has been suggested that either a Cpd 0 or Cpd 1 can perform oxidation of both the native and 3-F-Ty substrates.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Substrate Conformation Masquerades Two different Oxidants in Aromatic C-H and C-F bond activation by Heme-dependent Tyrosine Hydroxylase

Singh

Santos

Yadav

et al. 2022

Preprint

View full text Add to dashboard Cite

A recently discovered heme-dependent enzyme TyrH offers a green approach for functionalizing the high-strength C-H and C-F bonds in aromatic compounds. However, there is ambiguity regarding the nature of intermediates (Cpd 0 or Cpd I) involved in activating these bonds. Herein, using comprehensive MD Simulations and hybrid QM/MM calculations, we reveal that it is Compound I (Cpd I) that acts as the primary oxidant involved in the functionalization of both the C-F and C-H bonds. Our study shows that the His88 close to the catalytic site acts as a modulator of aromaticity and is essential to initiate the C-H and C-F bond activation. The reaction proceeds via the proton abstraction from the 4-OH group of the substrate by His88, which is coupled with an electron transfer to form a single-electron reduced Cpd I-like intermediate. This species then inserts the oxygen atom into the sp3 hybridized C-H and C-F bond of the substrate. Interestingly, our mechanistic study shows that the two different conformations of the substrate are actually responsible for the C-F and C-H functionalization, which masquerades as two different characters of oxidants involved in the reaction.

show abstract

An In Crystallo Reaction with an Engineered Cytochrome P450 Peroxygenase**

Lee,

Bruning,

Bell

2023

Chemistry A European J

View full text Add to dashboard Cite

The cytochrome P450 monooxygenases (CYPs) are a class of heme‐thiolate enzymes that insert oxygen into unactivated C‐H bonds. These enzymes can be converted into peroxygenases via protein engineering which enables their activity to occur using hydrogen peroxide (H2O2) without the requirement for additional nicotinamide co‐factors or partner proteins. Here, we demonstrate that soaking crystals of an engineered P450 peroxygenase with H2O2 enables the enzymatic reaction to occur within the crystal. Crystals of the designed P450 peroxygenase, the T252E mutant of CYP199A4, in complex with 4‐methoxybenzoic acid were soaked with different concentrations of H2O2 for varying times to initiate the in crystallo O‐demethylation reaction. Crystal structures of T252E‐CYP199A4 showed a distinct loss of electron density that was consistent with the O‐demethylated metabolite, 4‐hydroxybenzoic acid. A new X‐ray crystal structure of this enzyme with the 4‐hydroxybenzoic acid product was obtained to enable comparison alongside the existing substrate‐bound structure. The visualisation of enzymatic catalysis in action is challenging in structural biology and the ability to intitiate the reactions of P450 enzymes, in crystallo by simply soaking crystals with H2O2 will enable new structural biology methods and techniques to be applied to study their mechanism of action.

show abstract

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

Cited by 19 publications

References 70 publications

Oxidative C−F Cleavage in Metalloenzymes and Model Compounds

Oxidative C−F Cleavage in Metalloenzymes and Model Compounds

Substrate Conformation Masquerades Two different Oxidants in Aromatic C-H and C-F bond activation by Heme-dependent Tyrosine Hydroxylase

An In Crystallo Reaction with an Engineered Cytochrome P450 Peroxygenase**

Contact Info

Product

Resources

About