The multifunctional globin dehaloperoxidase strikes again: Simultaneous peroxidase and peroxygenase mechanisms in the oxidation of EPA pollutants

Malewschik, T.; Serrano, V.S. de; McGuire, Ashlyn; Ghiladi, Reza A.

doi:10.1016/j.abb.2019.108079

Cited by 16 publications

(24 citation statements)

References 67 publications

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“…A possible candidate for such a heme-based oxidant is Cpd I, a ferryl-oxo coupled porphyrin cation radical, which is commonly invoked as the primary reactive intermediate in heme enzymes and promotes a wide spectrum of oxidative chemistries. , In the case of His-ligated heme enzymes, Cpd I is thought to prefer ET rather than hydrogen atom transfer (HAT) due to the low p K a of the corresponding compound II (Cpd II, a ferryl-oxo with a neutral porphyrin) . A known example is DHP, which utilizes ET to activate aromatic substrates through peroxygenase-like or peroxidase-based mechanism. , The substrate binding conformation in TyrH shown in this work unambiguously excludes the possibility of HAT from either 4-hydroxyl or aromatic ortho carbons. The 4-OH of the substrate points to the δ edge of heme, away from the iron ion with a distance of nearly 6 Å (Figure B); while the distances from two ortho carbons to the iron center are 4.9 and 5.7 Å (Figure C).…”

Section: Discussionmentioning

confidence: 99%

“…44 A known example is DHP, which utilizes ET to activate aromatic substrates through peroxygenase-like or peroxidase-based mechanism. 45,46 The substrate binding conformation in TyrH shown in this work unambiguously excludes the possibility of HAT from either 4-hydroxyl or aromatic ortho carbons. The 4-OH of the substrate points to the δ edge of heme, away from the iron ion with a distance of nearly 6 Å (Figure 7B); while the distances from two ortho carbons to the iron center are 4.9 and 5.7 Å (Figure 7C).…”

Section: ■ Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

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 QM/MM model was prepared on the basis of the X-ray structure of DHP B in the complex with the substrate 4-Cl-o-cresol (PDB ID: 6ONK, resolution of 1.50 Å) from the terebellid polychaete A. Ornata, which consists of two chains. 15 The overlap of the two chains is shown in Figure S1, which shows that chain A (in purple) and chain B (in blue) are identical. Therefore, chain A was chosen to construct the computational model.…”

Section: Computational Detailsmentioning

confidence: 99%

“…14 In 2019, the X-ray crystal structures of DHP B in the complex with 4-X-o-cresol (X = F, Cl, Br, and NO 2 ) were further obtained. 15 DHP can be defined as a multifunctional catalytic hemoglobin, which has been proposed to employ four mechanisms for substrate oxidation to against toxic metabolites, including the electron-(peroxidase and oxidase) and Oatom (peroxygenase and oxygenase) transfer. 16 In addition, it was also suggested that the substrate itself plays a pivotal role in determining the activity (peroxidase, peroxygenase, oxidase, and/or oxygenase) of DHP.…”

Section: ■ Introductionmentioning

confidence: 99%

Computational Study of the Peroxygenase Mechanism Catalyzed by Hemoglobin Dehaloperoxidase Involved in the Degradation of Chlorophenols

et al. 2022

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The biochemical evidence showed that hemoglobin dehaloperoxidase (DHP B) from Amphitrite Ornata is a multifunctional hemoprotein that catalyzes both dehalogenation and hydroxylation of halophenols via the peroxidase and peroxygenase mechanism, respectively, which sets the basis for the degradation of halophenols. In the peroxygenase mechanism, the reaction was previously suggested to be triggered either by the hydrogen atom abstraction by the FeO center or by the proton abstraction by His55. To illuminate the peroxygenase mechanism of DHP B at the atomistic level, on the basis of the high-resolution crystal structure, computational models were constructed, and a series of quantum mechanical/molecular mechanical calculations have been performed. According to the calculation results, the pathway (Path a) initiated by the H-abstraction by the FeO center is feasible. In another pathway (Path b), His55 can abstract the proton from the hydroxyl group of the substrate (4-Cl-o-cresol) to initiate the reaction; however, its feasibility depends on the prior electron transfer from the substrate to the porphyrin group. The rate-limiting step of Path a is the OH-rebound, which corresponds to an energy barrier of 14.7 kcal/mol at the quartet state. His55 acts as an acid–base catalyst and directly involves in the catalysis. Our mutant study indicates that His55 can be replaced by other titratable residues. These findings may provide useful information for further understanding of the catalytic reaction of DHP B and for the design of enzymes in the degradation of pollutants, in particular, halophenols.

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“…Named dehaloperoxidase (DHP; Chen et al, 1996;Zhang et al, 1996), this O 2 -transport protein (Weber et al, 1977;Sun et al, 2014) is capable of oxidizing a wide array of substrates by either electron or O-atom transfer. These substrates include mono-, di-and trihalophenols (Chen et al, 1996), haloindoles (Barrios et al, 2014), pyrroles (McCombs, Smirnova et al, 2017), (halo)guaiacols (McGuire et al, 2018), nitrophenols (McCombs et al, 2016 and cresols (Malewschik et al, 2019). DHP can also strongly bind azoles (McCombs, Moreno-Chicano et al, 2017).…”

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confidence: 99%

Complementarity of neutron, XFEL and synchrotron crystallography for defining the structures of metalloenzymes at room temperature

Moreno-Chicano

Carey

Axford

et al. 2022

IUCrJ

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Room-temperature macromolecular crystallography allows protein structures to be determined under close-to-physiological conditions, permits dynamic freedom in protein motions and enables time-resolved studies. In the case of metalloenzymes that are highly sensitive to radiation damage, such room-temperature experiments can present challenges, including increased rates of X-ray reduction of metal centres and site-specific radiation-damage artefacts, as well as in devising appropriate sample-delivery and data-collection methods. It can also be problematic to compare structures measured using different crystal sizes and light sources. In this study, structures of a multifunctional globin, dehaloperoxidase B (DHP-B), obtained using several methods of room-temperature crystallographic structure determination are described and compared. Here, data were measured from large single crystals and multiple microcrystals using neutrons, X-ray free-electron laser pulses, monochromatic synchrotron radiation and polychromatic (Laue) radiation light sources. These approaches span a range of 18 orders of magnitude in measurement time per diffraction pattern and four orders of magnitude in crystal volume. The first room-temperature neutron structures of DHP-B are also presented, allowing the explicit identification of the hydrogen positions. The neutron data proved to be complementary to the serial femtosecond crystallography data, with both methods providing structures free of the effects of X-ray radiation damage when compared with standard cryo-crystallography. Comparison of these room-temperature methods demonstrated the large differences in sample requirements, data-collection time and the potential for radiation damage between them. With regard to the structure and function of DHP-B, despite the results being partly limited by differences in the underlying structures, new information was gained on the protonation states of active-site residues which may guide future studies of DHP-B.

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The multifunctional globin dehaloperoxidase strikes again: Simultaneous peroxidase and peroxygenase mechanisms in the oxidation of EPA pollutants

Cited by 16 publications

References 67 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

Computational Study of the Peroxygenase Mechanism Catalyzed by Hemoglobin Dehaloperoxidase Involved in the Degradation of Chlorophenols

Complementarity of neutron, XFEL and synchrotron crystallography for defining the structures of metalloenzymes at room temperature

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