Protein oxidation of cytochrome c by reactive halogen species enhances its peroxidase activity
Open accessAbstract
Reactive halogen species (RHS; X(2) and HOX, where X represents Cl, Br, or I) are metabolites mediated by neutrophil activation and its accompanying respiratory burst. We have investigated the interaction between RHS and mitochondrial cytochrome c (cyt c) by using electrospray mass spectrometry and electron spin resonance (ESR). When the purified cyt c was reacted with an excess amount of hypochlorous acid (HOCl) at pH 7.4, the peroxidase activity of cyt c was increased by 4.5-, 6.9-, and 8.6-fold at molar ratios (HOCl/cyt c) of 2, 4, and 8, respectively. In comparison with native cyt c, the mass spectra obtained from the HOCl-treated cyt c revealed that oxygen is covalently incorporated into the protein as indicated by molecular ions of m/z = 12,360 (cyt c), 12,376 (cyt c + O), and 12,392 (cyt c + 2O). Using tandem mass spectrometry, a peptide (obtained from the tryptic digests of HOCl-treated cyt c) corresponding to the amino acid sequence MIFAGIK, which contains the methionine that binds to the heme, was identified to be involved in the oxygen incorporation. The location of the oxygen incorporation was unequivocally determined to be the methionine residue, suggesting that the oxidation of heme ligand (Met-80) by HOCl results in the enhancement of peroxidase activity of cyt c. ESR spectroscopy of HOCl-oxidized cyt c, when reacted with H(2)O(2) in the presence of the nitroso spin trap 2-methyl-2-nitrosopropane (MNP), yielded more immobilized MNP/tyrosyl adduct than native cyt c. In the presence of H(2)O(2), the peroxidase activity of HOCl-oxidized cyt c exhibited an increasing ability to oxidize tyrosine to tyrosyl radical as measured directly by fast flow ESR. Titration of both native cyt c and HOCl-oxidized cyt c with various amounts of H(2)O(2) indicated that the latter has a decreased apparent K(m) for H(2)O(2), implicating that protein oxidation of cyt c increases its accessibility to H(2)O(2). HOCl-oxidized cyt c also displayed an impaired ability to support oxygen consumption by the purified mitochondrial cytochrome c oxidase, suggesting that protein oxidation of cyt c may break the electron transport chain and inhibit energy transduction in mitochondria.
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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, tyrosines are nitrated, or the cytochrome interacts with anionic phospholipids.
“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 [65]
In cytochrome c, transition from hexa- to pentacoordination is induced by Met-80 oxidation, Tyr-67 nitration, and interaction with anionic lipids such as cardiolipin.
“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 [77]
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Self-citation
- Authors
- Chen, Y.-R., Deterding, L. J., Sturgeon, B. E., Tomer, K. B., & Mason, R. P.
- Affiliations
- National Institutes of Health (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 33
- Pages
- 29781-29791
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2065463667
- Cited by
- 110
- References
- 58
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 6 · 2012: 5
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- cytochrome c, reactive halogen species, hypochlorous acid, peroxidase activity, protein oxidation, oxygen incorporation, tyrosyl radical, hydrogen peroxide, neutrophil respiratory burst, heme-protein interaction, 2-methyl-2-nitrosopropane
- MeSH terms
- Cytochrome c Group, Electron Spin Resonance Spectroscopy, Halogens, Oxidation-Reduction, Peroxidases, Trypsin, Tyrosine, Spectrometry, Mass, Electrospray Ionization
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