A kinetic study of the mechanism of conversion of α-hydroxyheme to verdoheme while bound to heme oxygenase

Sakamoto, Hiroshi; Takahashi, Keníchi; Higashimoto, Yuichiro; Harada, Saori; Palmer, Graham; Noguchi, Masato

doi:10.1016/j.bbrc.2005.08.176

Cited by 14 publications

(12 citation statements)

References 13 publications

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“…The first step is the oxidation of heme to α-hydroxyheme, requiring O 2 and two electrons [6][7][8]. The second step, also requiring O 2 and an electron, is the formation of ferrous α-verdoheme from α-hydroxyheme with the concomitant release of hydroxylated α-meso carbon as CO [9][10][11][12]. The third step is the conversion of ferrous α-verdoheme to a ferric biliverdin-iron chelate for which, once again, O 2 and three electrons are required [13].…”

Section: Introductionmentioning

confidence: 99%

Electrochemical reduction of ferrous α-verdoheme in complex with heme oxygenase-1

Satō

Higashimoto

Sakamoto

et al. 2007

Journal of Inorganic Biochemistry

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The heme oxygenase (HO) reaction consists of three successive oxygenation reactions, i.e. heme to α-hydroxyheme, α-hydroxyheme to verdoheme, and verdoheme to biliverdin-iron chelate. Of these, the least understood step is the conversion of verdoheme to biliverdin-iron chelate. For the cleavage of the oxaporphyrin ring of ferrous verdoheme, involvement of a verdoheme π-neutral radical has been proposed. To probe this hypothetical mechanism in the HO reaction, we performed electrochemical reduction of ferrous verdoheme complexed with rat HO-1 under anaerobic conditions. On the basis of the electrochemical spectral changes, the midpoint potential for the oneelectron reduction of the oxaporphyrin ring of ferrous verdoheme was found to be −0.47 ± 0.01 V vs the normal hydrogen electrode (NHE). Because this potential is far lower than those of both flavins of NADPH-cytochrome P450 reductase, and of NADPH, it is concluded that the one-electron reduction of the oxaporphyrin ring of ferrous verdoheme is unlikely to occur and that the formation of the π-neutral radical cannot be the initial step in the degradation of verdoheme by HO. Rather, it appears more reasonable to consider an alternative mechanism in which binding of O 2 to the ferrous iron of verdoheme is the first step in the degradation of verdoheme.

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Section: Introductionmentioning

confidence: 99%

Electrochemical reduction of ferrous α-verdoheme in complex with heme oxygenase-1

Satō

Higashimoto

Sakamoto

et al. 2007

Journal of Inorganic Biochemistry

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“…The binding of oxygen to the native heme oxygenase with ferrous α-meso-hydroxyheme leads to rapid formation of verdoheme. 44,56 If this holds for our synthetic proteins, it is one of the preceding reactions that controls the observed rate constant k 1 . Two observations indicated that the first step of Scheme 3 is rate-limiting.…”

Section: Discussionmentioning

confidence: 95%

Detection of Heme Oxygenase Activity in a Library of Four-helix Bundle Proteins: Towards the de Novo Synthesis of Functional Heme Proteins

Monien¹,

Drepper²,

Sommerhalter³

et al. 2007

Journal of Molecular Biology

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“…In contrast to meso -hydroxyheme interacting with O 2 prior addition of a reducing equivalent [54,58] it was previously proposed that reduction of meso -hydroxyheme to Fe(II)-verdoheme was required prior to O 2 binding [57]. However, the reaction of Fe(III)- meso -hydroxyheme with O 2 is significantly faster than reduction of the iron, suggesting under physiological conditions the formation of Fe(III)-verdoheme precedes the injection of a reducing equivalent to yield Fe(II)-verdoheme [59]. …”

Section: Introductionmentioning

confidence: 99%

“…The conflicting reports surrounding the structure of the Fe(II)-verdoheme HO distal pocket are most likely due to the unstable nature of the Fe(II)-verdoheme intermediate. Although Fe(II)-verdoheme was reported to be five coordinate in the initial crystal structure previous early and recent spectroscopic studies suggest Fe(II)-verdoheme is six coordinate and low spin [59,82,83]. Although challenging many of the remaining questions regarding the mechanism of Fe(II)-verdoheme conversion to biliverdin will be answered through detailed spectroscopic analysis of the electronic structure of Fe(II)-verdoheme and its O 2 -reacted intermediates.…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenation and the widening paradigm of heme degradation

Wilks

Heinzl

2014

Archives of Biochemistry and Biophysics

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Heme degradation through the action of heme oxygenase (HO) is unusual in that it utilizes heme as both a substrate and cofactor for its own degradation. HO catalyzes the oxygen-dependent degradation of heme to biliverdin with the release of CO and "free" iron. The characterization of HO enzymes from humans to bacteria reveals a similar overall structural fold that contributes to the unique reaction manifold. The heme oxygenases share a similar heme-dependent activation of O2 to the ferric hydroperoxide as that of the cytochrome P450s and peroxidases. However, whereas the P450s promote cleavage of the ferric hydroperoxide OO bond to the oxoferryl species the HOs stabilize the ferric hydroperoxide promoting hydroxylation at the heme edge. The alternate reaction pathway in HO is achieved through the conformational flexibility and extensive hydrogen bond network within the heme binding site priming the heme for hydroxylation. Until recently it was believed that all heme degrading enzymes converted heme to biliverdin and iron, with the release of carbon monoxide (CO). However, the recent discovery of the bacterial IsdG-like heme degrading proteins of Staphylococcus aureus, Bacillus anthracis and Mycobacterium tuberculosis has expanded the reaction manifold of heme oxidation. Characterization of the heme degradation products in the IsdG-like reaction suggests a mechanism distinct from the classical HOs. In the following review we will discuss the structure-function of the canonical HOs as it relates to the emerging alternate reaction manifold of the IsdG-like proteins.

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A kinetic study of the mechanism of conversion of α-hydroxyheme to verdoheme while bound to heme oxygenase

Cited by 14 publications

References 13 publications

Electrochemical reduction of ferrous α-verdoheme in complex with heme oxygenase-1

Electrochemical reduction of ferrous α-verdoheme in complex with heme oxygenase-1

Detection of Heme Oxygenase Activity in a Library of Four-helix Bundle Proteins: Towards the de Novo Synthesis of Functional Heme Proteins

Heme oxygenation and the widening paradigm of heme degradation

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