Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins.
Open accessAbstract
Phagocytes generate H2O2 for use by a secreted heme enzyme, myeloperoxidase, to kill invading bacteria, viruses, and fungi. We have explored the possibility that myeloperoxidase might also convert L-tyrosine to a radical catalyst that cross-links proteins. Protein-bound tyrosyl residues exposed to myeloperoxidase, H2O2, and L-tyrosine were oxidized to o,o'-dityrosine, a stable product of the tyrosyl radical. The cross-linking reaction required L-tyrosine but was independent of halide and free transition metal ions; the heme poisons azide and aminotriazole were inhibitory. Activated neutrophils likewise converted polypeptide tyrosines to dityrosine. The pathway for oxidation of peptide tyrosyl residues was dependent upon L-tyrosine and was inhibited by heme poisons and catalase. Dityrosine synthesis was little affected by plasma concentrations of Cl- and amino acids, suggesting that the reaction pathway might be physiologically relevant. The requirement for free L-tyrosine and H2O2 for dityrosine formation and the inhibition by heme poisons support the hypothesis that myeloperoxidase catalyzes the cross-linking of proteins by a peroxidative mechanism involving tyrosyl radical. In striking contrast to the pathways generally used to study protein oxidation in vitro, the reaction does not require free metal ions. We speculate that protein dityrosine cross-linking by myeloperoxidase may play a role in bacterial killing or injuring normal tissue. The intense fluorescence and stability of biphenolic compounds may allow dityrosine to act as a marker for proteins oxidatively damaged by myeloperoxidase in phagocyte-rich inflammatory lesions.
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The main product of tyrosyl radical reaction after enolization is the fluorescent protein crosslink ortho,ortho-dityrosine.
“After enolization, the main product of this reaction is the fluorescent protein crosslink ortho,ortho-dityrosine [23].”
From Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases (2021) · cites this paper as [23]
The Introduction (page not provided) calls o,o′-dityrosine the major product of the tyrosyl-radical reaction, and the Methods describe protein-bound dityrosine measured by fluorescence. Our copy does not describe enolization as a step preceding its formation. (LLM, conf=0.88)
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Research works printed but not linked: 1
- Foerder, C. A., and B. M. Schapiro. 1977. Release of ovoperoxidase from sea urchin eggs hardens the fertilization membrane with tyrosine crosslinks. Proc. Natl. Acad. Sci. USA. 74:4214-4218.
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- Authors
- Heinecke, J. W., Li, W., Francis, G. A., & Goldstein, J. A.
- Affiliations
- Washington University in St. Louis (US)
- University of Washington (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1993-06-01
- Volume
- 91
- Issue
- 6
- Pages
- 2866-2872
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC443356
- OpenAlex
- W1969878412
- Cited by
- 354
- References
- 0
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 11 · 2021: 10 · 2020: 13 · 2019: 6 · 2018: 11 · 2017: 3 · 2016: 8 · 2015: 9 · 2014: 14 · 2013: 15 · 2012: 10
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Fondation pour la Recherche Médicale
- Medical Research Council Canada
- National Institutes of Health (5p60am020579-08, 5r01hd029920-05, 5p41rr000954-34)
- Medical Research Council
- National Center for Research Resources (RR 00954)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD-29920)
- 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
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- myeloperoxidase, tyrosyl radical, dityrosine, tyrosine, hydrogen peroxide, neutrophils, phagocytes, heme enzymes, peroxidase mechanism, protein oxidation, oxidative damage markers, bacterial killing
- MeSH terms
- Amino Acid Sequence, Cross-Linking Reagents, Dipeptides, Free Radicals, Humans, Molecular Sequence Data, Peroxidase, Neutrophils, Oligopeptides, Oxidation-Reduction, Serum Albumin, Bovine, Tyrosine
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