Verdohemochrome IX alpha: preparation and oxidoreductive cleavage to biliverdin IX alpha.

Saito, Setsuo; Itano, Harvey A.

doi:10.1073/pnas.79.5.1393

Cited by 56 publications

(58 citation statements)

References 17 publications

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“…To our knowledge, this work reports the first examination of the reaction between the ferrous verdoheme-HO-1 complex and H 2 O 2 . Similar H 2 O 2 -dependent verdoheme degradations have been reported for model complexes of ferrous verdoheme in organic media (13,14).…”

Section: Discussionsupporting

confidence: 58%

“…5. The biliverdin formation in the O 2 -and H 2 O 2 -dependent reactions formally requires four and two electrons, respectively (13). Indeed the H 2 O 2 reaction consumes smaller amounts of NADPH for the biliverdin formation than the O 2 reaction as judged from the NADPH absorbance decrease at 340 nm (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Non-enzymatic conversion of verdoheme to biliverdin can be performed by hydrolysis or by redox reactions using O 2 or H 2 O 2 (13)(14)(15)(16). Despite the chemical versatility, HO has been considered to exclusively utilize O 2 as an oxygen source for the verdoheme degradation.…”

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confidence: 99%

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O2- and H2O2-dependent Verdoheme Degradation by Heme Oxygenase

Matsui

Nakajima

Fujii

et al. 2005

Journal of Biological Chemistry

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Heme oxygenase (HO) catalyzes the catabolism of heme to biliverdin, CO, and a free iron through three successive oxygenation steps. The third oxygenation, oxidative degradation of verdoheme to biliverdin, has been the least understood step despite its importance in regulating HO activity. We have examined in detail the degradation of a synthetic verdoheme IX␣ complexed with rat HO-1. Our findings include: 1) HO degrades verdoheme through a dual pathway using either O 2 or H 2 O 2 ; 2) the verdoheme reactivity with O 2 is the lowest among the three O 2 reactions in the HO catalysis, and the newly found H 2 O 2 pathway is ϳ40-fold faster than the O 2 -dependent verdoheme degradation; 3) both reactions are initiated by the binding of O 2 or H 2 O 2 to allow the first direct observation of degradation intermediates of verdoheme; and 4) Asp 140 in HO-1 is critical for the verdoheme degradation regardless of the oxygen source. On the basis of these findings, we propose that the HO enzyme activates O 2 and H 2 O 2 on the verdoheme iron with the aid of a nearby water molecule linked with Asp 140 . These mechanisms are similar to the well established mechanism of the first oxygenation, meso-hydroxylation of heme, and thus, HO can utilize a common architecture to promote the first and third oxygenation steps of the heme catabolism. In addition, our results infer the possible involvement of the H 2 O 2 -dependent verdoheme degradation in vivo, and potential roles of the dual pathway reaction of HO against oxidative stress are proposed. Heme oxygenase (HO)2 catalyzes regiospecific conversion of heme (iron-protoporphyrin IX) to biliverdin IX␣, CO, and a free iron (1-3). In mammals, HO exists as two isoforms, an inducible HO-1 (M r 33,000) and a constitutive HO-2 (M r 36,000). Biliverdin is immediately reduced by biliverdin reductase to bilirubin, a potent antioxidant. Primary functions of the mammalian HO enzymes are excess heme catabolism, antioxidant defense, and generation of CO, a physiological messenger molecule (2, 4 -7). The HO enzymes have been identified in higher plants, cyanobacteria, and some pathogenic bacteria (8 -11). The heme degradation by HO proceeds through three successive oxygenation steps involving the uptake of a total of seven electrons (Fig. 1). The O 2 activations in the HO catalysis are performed by the substrate heme and its catabolic intermediates (2, 3). The first step of the HO reaction is the regiospecific hydroxylation of the porphyrin ␣-meso-carbon atom (Fig. 1). The resulting ␣-meso-hydroxyheme reacts with another O 2 to yield verdoheme and CO. Further O 2 activation cleaves the heme macrocycle to afford a ferric biliverdin complex. The final one-electron reduction releases a ferrous iron and then biliverdin. The biliverdin release from HO is the slowest step in the HO catalysis but is drastically accelerated by biliverdin reductase (12). The rate-determining step of the heme degradation in vivo is considered to be the conversion of verdoheme to the ferric biliverdin complex (12). Despite ...

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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O2- and H2O2-dependent Verdoheme Degradation by Heme Oxygenase

Matsui

Nakajima

Fujii

et al. 2005

Journal of Biological Chemistry

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“…The products were extracted into chloroform, and the solvent was removed under a stream of nitrogen. The verdoheme product formed in the H 2 O 2 -dependent reaction was hydrolytically converted to biliverdin by the method of Saito and Itano (20). The biliverdin was extracted into chloroform and reduced to dryness.…”

Section: Methodsmentioning

confidence: 99%

Degradation of Heme in Gram-Negative Bacteria: the Product of the hemO Gene of Neisseriae Is a Heme Oxygenase

2000

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A full-length heme oxygenase gene from the gram-negative pathogen Neisseria meningitidis was cloned and expressed in Escherichia coli. Expression of the enzyme yielded soluble catalytically active protein and caused accumulation of biliverdin within the E. coli cells. The purified HemO forms a 1:1 complex with heme and has a heme protein spectrum similar to that previously reported for the purified heme oxygenase (HmuO) from the gram-positive pathogen Corynebacterium diphtheriae and for eukaryotic heme oxygenases. The overall sequence identity between HemO and these heme oxygenases is, however, low. In the presence of ascorbate or the human NADPH cytochrome P450 reductase system, the heme-HemO complex is converted to ferric-biliverdin IX␣ and carbon monoxide as the final products. Homologs of the hemO gene were identified and characterized in six commensal Neisseria isolates, Neisseria lactamica, Neisseria subflava, Neisseria flava, Neisseria polysacchareae, Neisseria kochii, and Neisseria cinerea. All HemO orthologs shared between 95 and 98% identity in amino acid sequences with functionally important residues being completely conserved. This is the first heme oxygenase identified in a gram-negative pathogen. The identification of HemO as a heme oxygenase provides further evidence that oxidative cleavage of the heme is the mechanism by which some bacteria acquire iron for further use.

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“…It has been well known that hydrolysis of verdoheme to biliverdin can take place in acidic solution [11]. However, the enzymatic degradation of verdoheme to ferric biliverdin-iron chelate by HO requires O 2 and reducing equivalents [16][17][18] and both lactam oxygen atoms present in the biliverdin-iron chelate derive from molecular oxygen [19,20].…”

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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Verdohemochrome IX alpha: preparation and oxidoreductive cleavage to biliverdin IX alpha.

Cited by 56 publications

References 17 publications

O2- and H2O2-dependent Verdoheme Degradation by Heme Oxygenase

O2- and H2O2-dependent Verdoheme Degradation by Heme Oxygenase

Degradation of Heme in Gram-Negative Bacteria: the Product of the hemO Gene of Neisseriae Is a Heme Oxygenase

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

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