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Cytochrome c Nitration by Peroxynitrite
Open accessAbstract
Peroxynitrite (ONOO(-)), the product of superoxide (O(2)) and nitric oxide (.NO) reaction, inhibits mitochondrial respiration and can stimulate apoptosis. Cytochrome c, a mediator of these two aspects of mitochondrial function, thus represents an important potential target of ONOO(-) during conditions involving accelerated rates of oxygen radical and.NO generation. Horse heart cytochrome c(3+) was nitrated by ONOO(-), as indicated by spectral changes, Western blot analysis, and mass spectrometry. A dose-dependent loss of cytochrome c(3+) 695 nm absorption occurred, inferring that nitration of a critical heme-vicinal tyrosine (Tyr-67) promoted a conformational change, displacing the Met-80 heme ligand. Nitration was confirmed by cross-reactivity with a specific antibody against 3-nitrotyrosine and by increased molecular mass compatible with the addition of a nitro-(-NO(2)) group. Mass analysis of tryptic digests indicated the preferential nitration of Tyr-67 among the four conserved tyrosine residues in cytochrome c. Cytochrome c(3+) was more extensively nitrated than cytochrome c(2+) because of the preferential oxidation of the reduced heme by ONOO(-). Similar protein nitration patterns were obtained by ONOO(-) reaction in the presence of carbon dioxide, whereupon secondary nitrating species arise from the decomposition of the nitroso-peroxocarboxylate (ONOOCO(2)(-)) intermediate. Peroxynitrite-nitrated cytochrome c displayed significant changes in redox properties, including (a) increased peroxidatic activity, (b) resistance to reduction by ascorbate, and (c) impaired support of state 4-dependent respiration in intact rat heart mitochondria. These results indicate that cytochrome c nitration may represent both oxidative and signaling events occurring during .NO- and ONOO(-)-mediated cell injury.
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“Importantly, protein nitration can also occur through the reaction of nitrite with heme proteins in the presence of hydrogen peroxide (153, 154).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [153]
In the citing paper
“Similar to Ngb, the heme iron of cytochrome c is predominately hexacoordinate, but can become pentacoordinate when the iron-methionine bond is ruptured which occurs when the methionine is oxidized [65, 66], tyrosines are nitrated [67, 68], or the cytochrome interacts with anionic phospholipids such as those present in the inner membrane of the mitochondria [69–71].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [68]
In the citing paper
“In the case of cytochrome c, transition from hexa- to pentacoordination has been shown to be induced by Met-80 oxidation [77], Tyr-67 nitration [78] and by interaction with anionic lipids such as cardiolipin [79].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [78]
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Metadata
- Authors
- Cassina, A. M., Hodara, R., Souza, J. M., Thomson, L., Castro, L., Ischiropoulos, H., Freeman, B. A., & Radi, R.
- Affiliations
- Universidad de la República de Uruguay (UY)
- Children's Hospital of Philadelphia (US)
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 275
- Issue
- 28
- Pages
- 21409-21415
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2009279488
- Cited by
- 354
- References
- 57
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 2 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 5 · 2015: 5 · 2014: 17 · 2013: 9 · 2012: 22
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG 13966, R01AG013966)
- National Heart, Lung, and Blood Institute (HL54926, R01HL054926)
- Fogarty International Center (R03-TW0099)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- cytochrome c, peroxynitrite, nitration, nitrotyrosine, mitochondrial respiration, apoptosis, nitric oxide, superoxide, redox properties, heart mitochondria, oxidative stress
- MeSH terms
- Animals, Binding Sites, Cytochrome c Group, Horses, Kinetics, Mitochondria, Heart, Models, Molecular, Molecular Conformation, Nitrates, Peptide Mapping, Protein Conformation, Spectrophotometry, Mass Spectrometry, Trypsin, Oxidants, Rats
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