Reaction of Metmyoglobin with Hydrogen Peroxide

George, Philip; Irvine, D. H.

doi:10.1038/168164b0

Cited by 64 publications

(35 citation statements)

References 5 publications

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“…Several studies suggest that the reactions between myoglobin and hydrogen peroxide are a key determinant of oxidative damage in the ischemic and then reoxygenated heart (35,36). These reactions result in generation of ferryl myoglobin (MbFe IV ϭ O) and the globin radical ( ⅐ MbFe IV ϭ O) (35,37). Both species are strong oxidants, which may induce lipid and protein peroxidation.…”

Section: Discussionmentioning

confidence: 99%

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Hendgen‐Cotta

Merx

Shiva

et al. 2008

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

367

353

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The nitrite anion is reduced to nitric oxide (NO • ) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO • signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ( +/+ ) and knockout ( −/− ) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO • generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO • generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO • by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin +/+ but not in myoglobin −/− hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin +/+ mice, whereas in myoglobin −/− mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation. myoglobin knockout mice

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Section: Discussionmentioning

confidence: 99%

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Hendgen‐Cotta

Merx

Shiva

et al. 2008

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

367

353

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“…For example, the bacterial hemoglobin from Vitreoscilla shows peroxidase activity similar to that of HRP, 8 and it has been known for many years that human hemoglobin (Hb) is a better peroxidase than human myoglobin (Mb), but no physiological role for this activity is known. 9,10 Sperm whale Mb has been the subject of significant protein engineering, leading to significant peroxidase and peroxygenase activity in certain mutants. 11−13 Although myoglobins can be engineered to have moderately high peroxidase activity, they are not competitive with functional peroxidases.…”

Section: ■ Introductionmentioning

confidence: 99%

Distinct Enzyme–Substrate Interactions Revealed by Two Dimensional Kinetic Comparison between Dehaloperoxidase-Hemoglobin and Horseradish Peroxidase

Zhao

Franzen

2015

J. Phys. Chem. B

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The time-resolved kinetics of substrate oxidation and cosubstrate H2O2 reduction by dehaloperoxidase-hemoglobin (DHP) on a seconds-to-minutes time scale was analyzed for peroxidase substrates 2,4,6-tribromophenol (2,4,6-TBP), 2,4,6-trichlorophenol (2,4,6-TCP), and ABTS. Substrates 2,4,6-TBP and 2,4,6-TCP show substrate inhibition at high concentration due to the internal binding at the distal pocket of DHP, whereas ABTS does not show substrate inhibition at any concentration. The data are consistent with an external binding site for the substrates with an internal substrate inhibitor binding site for 2,4,6-TBP and 2,4,6-TCP. We have also compared the kinetic behavior of horseradish peroxidase (HRP) in terms of kcat, Km(AH2) and Km(H2O2) using the same kinetic scheme. Unlike DHP, HRP does not exhibit any measurable substrate inhibition, consistent with substrate binding at the edge of heme near the protein surface at all substrate concentrations. The binding of substrates and their interactions with the heme iron were further compared between DHP and HRP using a competitive fluoride binding experiment, which provides a method for quantitative measurement of internal association constants associated with substrate inhibition. These experiments show the regulatory role of an internal substrate binding site in DHP from both a kinetic and competitive ligand binding perspective. The interaction of DHP with substrates as a result of internal binding actually stabilizes that protein and permits DHP to function under conditions that denature HRP. As a consequence, DHP is a tortoise, a slow but steady enzyme that wins the evolutionary race against the HRP-type of peroxidase, which is a hare, initially rapid, but flawed for this application because of the protein denaturation under the conditions of the experiment.

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“…Thus, Symons and Kappl and coworkers 9 proposed that the hydroperoxo-ferric-Mb intermediate produced by cryoreduction decays directly to high-spin ferric-Mb via a dissociative mechanism, whereas it is well known that the reaction between metMb and H 2 O 2 forms compound I which is very unstable and converts to the EPR-silent Mb compound II (Fe IV =O). [10][11][12][13][14][15] This raises the question whether the hydroperoxo-ferric intermediate formed during low-temperature cryoreduction/annealing is distinct from the intermediate formed during ambient-temperature reaction of metMb with H 2 O 2 .…”

Section: Introductionmentioning

confidence: 99%

Distinct Reaction Pathways Followed upon Reduction of Oxy-Heme Oxygenase and Oxy-Myoglobin as Characterized by Mössbauer Spectroscopy

et al. 2007

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Activation of O 2 by heme-containing monooxygenases generally commences with the common initial steps of reduction to the ferrous heme and binding of O 2 followed by a one-electron reduction of the O 2 -bound heme. Subsequent steps that generate reactive oxygen intermediates diverge and reflect the effects of protein control on the reaction pathway. In this study, Mössbauer and EPR spectroscopies were used to characterize the electronic states and reaction pathways of reactive oxygen intermediates generated by 77 K radiolytic cryoreduction and subsequent annealing of oxyheme oxygenase (HO) and oxy-myoglobin (Mb). The results confirm that one-electron reduction of (Fe II -O 2 )HO is accompanied by protonation of the bound O 2 to generate a low-spin (Fe III -O 2 H − )HO that undergoes self hydroxylation to form the α-meso-hydroxyhemin-HO product. In contrast, oneelectron reduction of (Fe II -O 2 )Mb yields a low-spin (Fe III -O 2 2− )Mb. Protonation of this intermediate generates (Fe III -O 2 H − )Mb, which then decays to a ferryl complex, (Fe IV =O 2− )Mb, that exhibits magnetic properties characteristic of the compound II species generated in the reactions of peroxide with heme peroxidases and with Mb. Generation of reactive high-valent states with ferryl species via hydroperoxo intermediates is believed to be the key oxygen-activation steps involved in the catalytic cycles of P450-type monooxygenases. The Mössbauer data presented here provide direct spectroscopic evidence supporting the idea that ferric-hydroperoxo hemes are indeed the precursors of the reactive ferryl intermediates. The fact that a ferryl intermediate does not accumulate in HO underscores the determining role played by protein structure in controlling the reactivity of reaction intermediates.

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Reaction of Metmyoglobin with Hydrogen Peroxide

Cited by 64 publications

References 5 publications

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Distinct Enzyme–Substrate Interactions Revealed by Two Dimensional Kinetic Comparison between Dehaloperoxidase-Hemoglobin and Horseradish Peroxidase

Distinct Reaction Pathways Followed upon Reduction of Oxy-Heme Oxygenase and Oxy-Myoglobin as Characterized by Mössbauer Spectroscopy

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