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Cited by 486Neutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stressNitric Oxide and Endothelin Effects

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Brennan, Marie-Luise, Wu, Weijia, Fu, Xiaoming, Shen, Zhongzhu, Song, Wei, Frost, Heather, Vadseth, Caryn, Narine, Laura +8 more·2002·Journal of Biological Chemistry
DOI 10.1074/jbc.m112400200
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Abstract

Nitrotyrosine is widely used as a marker of post-translational modification by the nitric oxide ((.)NO, nitrogen monoxide)-derived oxidant peroxynitrite (ONOO(-)). However, since the discovery that myeloperoxidase (MPO) and eosinophil peroxidase (EPO) can generate nitrotyrosine via oxidation of nitrite (NO(2)(-)), several questions have arisen. First, the relative contribution of peroxidases to nitrotyrosine formation in vivo is unknown. Further, although evidence suggests that the one-electron oxidation product, nitrogen dioxide ((*)NO(2)), is the primary species formed, neither a direct demonstration that peroxidases form this gas nor studies designed to test for the possible concomitant formation of the two-electron oxidation product, ONOO(-), have been reported. Using multiple distinct models of acute inflammation with EPO- and MPO-knockout mice, we now demonstrate that leukocyte peroxidases participate in nitrotyrosine formation in vivo. In some models, MPO and EPO played a dominant role, accounting for the majority of nitrotyrosine formed. However, in other leukocyte-rich acute inflammatory models, no contribution for either MPO or EPO to nitrotyrosine formation could be demonstrated. Head-space gas analysis of helium-swept reaction mixtures provides direct evidence that leukocyte peroxidases catalytically generate (*)NO(2) formation using H(2)O(2) and NO(2)(-) as substrates. However, formation of an additional oxidant was suggested since both enzymes promote NO(2)(-)-dependent hydroxylation of targets under acidic conditions, a chemical reactivity shared with ONOO(-) but not (*)NO(2). Collectively, our results demonstrate that: 1) MPO and EPO contribute to tyrosine nitration in vivo; 2) the major reactive nitrogen species formed by leukocyte peroxidase-catalyzed oxidation of NO(2)(-) is the one-electron oxidation product, (*)NO(2); 3) as a minor reaction, peroxidases may also catalyze the two-electron oxidation of NO(2)(-), producing a ONOO(-)-like product. We speculate that the latter reaction generates a labile Fe-ONOO complex, which may be released following protonation under acidic conditions such as might exist at sites of inflammation.

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  • Protein nitration can occur through other mechanisms not directly involving the reaction of NO and O2 ̇̄, such as that of nitrite with the enzyme myeloperoxidase.

    “It is important to also realize that protein nitration can occur through other mechanisms not directly involving the reaction of NO and O2˙̄ such as that of nitrite with the enzyme myeloperoxidase (53).”

    From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [53]

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  1. Evans, T. J., Buttery, L. D., Carpenter, A., Springall, D. R., Polak, J. M., and Cohen, J. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9553-9558

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Authors
Brennan, M.-L., Wu, W., Fu, X., Shen, Z., Song, W., Frost, H., Vadseth, C., Narine, L., Lenkiewicz, E., Borchers, M. T., Lusis, A. J., Lee, J. J., Lee, N. A., Abu-Soud, H. M., Ischiropoulos, H., & Hazen, S. L.
Affiliations
  • Cleveland Clinic (US)
  • Children's Hospital of Philadelphia (US)
  • Mayo Clinic (US)
  • University of California, Los Angeles (US)
Corresponding author
Hazen, Stanley L.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-05
Volume
277
Issue
20
Pages
17415-17427
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m112400200
OpenAlex
W2116835524
Cited by
486
References
65
Citations by year
2026: 6 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 5 · 2020: 15 · 2019: 5 · 2018: 16 · 2017: 17 · 2016: 15 · 2015: 8 · 2014: 22 · 2013: 23 · 2012: 14
FWCI
16.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Cleveland Clinic
  • Cleveland Clinic Foundation
  • National Institutes of Health (5r01hl060793-02, 5r01hl065228-17, HL30568)
  • National Heart, Lung, and Blood Institute (HL-65228, HL3 0568, HL61878, HL 62526, HL54926, P01HL030568, R01HL054926, R01HL061878, HL-60793, R01HL062526)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
nitrotyrosine, peroxynitrite, myeloperoxidase, eosinophil peroxidase, nitrite oxidation, one-electron oxidation, reactive nitrogen species, leukocyte peroxidase, acute inflammation
MeSH terms
Animals, Candidiasis, Hydrogen Peroxide, Leukocytes, Mice, Inbred C57BL, Peroxidase, Nitrites, Nitrogen Dioxide, Oxidation-Reduction, Tyrosine, Mice, Knockout, Reactive Nitrogen Species, Mice

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