A catalytic di-heme
            <i>bis</i>
            -Fe(IV) intermediate, alternative to an Fe(IV)=O porphyrin radical

Li, Xianghui; Fu, Rong; Lee, Sheeyong; Krebs, Carsten; Davidson, Victor L.; Liu, Aimin

doi:10.1073/pnas.0801643105

Cited by 85 publications

(223 citation statements)

References 36 publications

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“…The NIR region of the electronic absorption spectrum of the bis-Fe (IV) species was not explored in previous studies (13,15,16). Inspection of this region revealed that a broad band centered at 950 nm developed upon addition of H 2 O 2 to diferric MauG concomitant with the previously observed changes in the visible region of the spectrum ( Fig.…”

Section: Resultsmentioning

confidence: 87%

“…1A). Previously, we reported the presence of a radical species detectable by EPR spectroscopy within the same time window as the one in which the bis-Fe(IV) species was observed (13). This radical species, representing only a few percent of the oxidized protein, was proposed to be located on Trp93 (13).…”

mentioning

confidence: 97%

“…Despite being a highly potent oxidant, the bis-Fe(IV) species displays extraordinary stability in the absence of preMADH, with a half-life of several minutes (13,15), rather than permanently oxidizing its own aromatic residues, such as Trp93, Trp199, and the heme ligand Tyr294. In this study, an NIR electronic absorption feature was observed in bis-Fe(IV) MauG.…”

mentioning

confidence: 99%

“…Our recent work has shown that each two-electron oxidation reaction proceeds via a high-valence bis-Fe(IV) intermediate, in which Heme 5C is present as Fe(IV)=O, and Heme 6C as Fe(IV) with the axial histidine-tyrosine ligand set retained (Fig. 1C) (13).…”

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confidence: 99%

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Tryptophan-mediated charge-resonance stabilization in the bis -Fe(IV) redox state of MauG

Geng

Dornevil

Davidson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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102

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The diheme enzyme MauG catalyzes posttranslational modifications of a methylamine dehydrogenase precursor protein to generate a tryptophan tryptophylquinone cofactor. The MauG-catalyzed reaction proceeds via a bis -Fe(IV) intermediate in which one heme is present as Fe(IV)=O and the other as Fe(IV) with axial histidine and tyrosine ligation. Herein, a unique near-infrared absorption feature exhibited specifically in bis -Fe(IV) MauG is described, and evidence is presented that it results from a charge-resonance-transition phenomenon. As the two hemes are physically separated by 14.5 Å, a hole-hopping mechanism is proposed in which a tryptophan residue located between the hemes is reversibly oxidized and reduced to increase the effective electronic coupling element and enhance the rate of reversible electron transfer between the hemes in bis -Fe(IV) MauG. Analysis of the MauG structure reveals that electron transfer via this mechanism is rapid enough to enable a charge-resonance stabilization of the bis -Fe(IV) state without direct contact between the hemes. The finding of the charge-resonance-transition phenomenon explains why the bis -Fe(IV) intermediate is stabilized in MauG and does not permanently oxidize its own aromatic residues.

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Section: Resultsmentioning

confidence: 87%

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confidence: 97%

mentioning

confidence: 99%

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confidence: 99%

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Tryptophan-mediated charge-resonance stabilization in the bis -Fe(IV) redox state of MauG

Geng

Dornevil

Davidson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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102

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“…The quadrupole splitting parameter of the TDO intermediate is noticeably greater than those of any other heme-based ferryl species but is much smaller than those of protonated basic ferryl species. The nearest value is found in MauG, another enzyme that oxidizes L-Trp inside a protein (67). A bis-Fe(IV) intermediate has been trapped from MauG, and one of the hemes is described as an oxyferryl species with a ⌬E Q value of 1.70 mm/s (67).…”

Section: Discussionmentioning

confidence: 99%

Enzyme Reactivation by Hydrogen Peroxide in Heme-based Tryptophan Dioxygenase

Gupta

Geng

et al. 2011

Journal of Biological Chemistry

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An intriguing mystery about tryptophan 2,3-dioxygenase is its hydrogen peroxide-triggered enzyme reactivation from the resting ferric oxidation state to the catalytically active ferrous form. In this study, we found that such an odd Fe(III) reduction by an oxidant depends on the presence of L-Trp, which ultimately serves as the reductant for the enzyme. In the peroxide reaction with tryptophan 2,3-dioxygenase, a previously unknown catalase-like activity was detected. A ferryl species (␦ ‫؍‬ 0.055 mm/s and ⌬E Q ‫؍‬ 1.755 mm/s) and a protein-based free radical (g ‫؍‬ 2.0028 and 1.72 millitesla linewidth) were characterized by Mössbauer and EPR spectroscopy, respectively. This is the first compound ES-type of ferryl intermediate from a heme-based dioxygenase characterized by EPR and Mössbauer spectroscopy. Density functional theory calculations revealed the contribution of secondary ligand sphere to the spectroscopic properties of the ferryl species. In the presence of L-Trp, the reactivation was demonstrated by enzyme assays and by various spectroscopic techniques. A Trp-Trp dimer and a monooxygenated L-Trp were both observed as the enzyme reactivation byproducts by mass spectrometry. Together, these results lead to the unraveling of an over 60-year old mystery of peroxide reactivation mechanism. These results may shed light on how a metalloenzyme maintains its catalytic activity in an oxidizing environment.Hemoproteins perform a wide range of biological functions, including oxygen transport, storage, electron transfer, monooxygenation, and reduction of dioxygen. However, they rarely express dioxygenase activity as their native biological function. Tryptophan 2,3-dioxygenase (TDO) 3 is the first described exception (1-3). This enzyme employs a b-type ferrous heme prosthetic group to catalyze the oxidative cleavage of the indole ring of L-Trp, converting it to N-formylkynurenine (NFK) (Scheme 1). This is the first and rate-limiting step of the kynurenine pathway of L-Trp metabolism, which oxidizes over 99% of L-Trp in mammalian intracellular and extracellular pools (2, 4 -9). The kynurenine pathway constitutes the major steps in biosynthesis of NAD, an essential redox cofactor in all living systems (5).TDO is a hepatic enzyme first discovered in rat liver extracts in 1936 (1). An analogous enzyme, indoleamine 2,3-dioxygenase (IDO), was isolated 31 years later from tissues other than the liver (10). Although both enzymes catalyze the same reaction, TDO is highly substrate-specific with L-Trp, whereas IDO presents a more relaxed specificity. TDO is a homotetramer with a total mass of ϳ134 kDa, whereas IDO is a monomeric protein. The two enzymes share only 14% sequence identity but conserve similar active site architectures (11-13). In addition to humans, TDO has also been found in other mammals, such as rats and mice, as well as in mosquitoes and bacteria (2, 5, 14 -18). Recently, a potential heme-dependent dioxygenase enzyme superfamily has been proposed (19). Moreover, several other heme-based proteins, such as my...

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Properties of the high‐spin heme of MauG are altered by binding of preMADH at the protein surface 40 Å away

Feng

Crudup

et al. 2017

FEBS Letters

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The diheme enzyme MauG catalyzes oxidative posttranslational modifications of a protein substrate, preMADH, that binds to the surface of MauG. The high-spin heme iron of MauG is located 40 Å from preMADH. The ferric heme is an equilibrium of five- and six-coordinate states. PreMADH binding increases the proportion of five-coordinate heme three-fold. On reaction of MauG with H2O2 both hemes become FeIV. In the absence of preMADH the hemes autoreduce to ferric in a multistep process involving multiple electron and proton transfers. Binding of preMADH in the absence of catalysis alters the mechanism of autoreduction of the ferryl heme. Thus, substrate binding alters the environment in the distal heme pocket of the high-spin heme over very long distance.

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A catalytic di-heme bis -Fe(IV) intermediate, alternative to an Fe(IV)=O porphyrin radical

Cited by 85 publications

References 36 publications

Tryptophan-mediated charge-resonance stabilization in the bis -Fe(IV) redox state of MauG

Tryptophan-mediated charge-resonance stabilization in the bis -Fe(IV) redox state of MauG

Enzyme Reactivation by Hydrogen Peroxide in Heme-based Tryptophan Dioxygenase

Properties of the high‐spin heme of MauG are altered by binding of preMADH at the protein surface 40 Å away

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