Detection of Bityrosine in Cataractous Human Lens Protein

García-Castiñeiras, Sixto; Dillon, James; Spector, Abraham

doi:10.1126/science.622574

Cited by 66 publications

(27 citation statements)

References 15 publications

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“…Both ultraviolet irradiation (8,28) and HO (9,10,19) can oxidize L-tyrosine to dityrosine. Although sunlight is thought to promote dityrosine formation in human cataracts (30) Mass Units amino acids were subjected to fast protein liquid chromatography at 1 ml/ min on a Mono Q HR5/5 column while collecting 2-ml fractions as described in Methods. Dityrosine (DiTyr) elutes from the column at the indicated ionic strength.…”

Section: Discussionmentioning

confidence: 99%

Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins.

Heinecke¹,

Li²,

Francis³

et al. 1993

J. Clin. Invest.

337

242

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Phagocytes generate H202 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, H202, and L-tyrosine were oxidized to oo'-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 H202 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. (J.Clin. Invest. 1993Invest. . 91:2866Invest. -2872

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Section: Discussionmentioning

confidence: 99%

Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins.

Heinecke¹,

Li²,

Francis³

et al. 1993

J. Clin. Invest.

337

242

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“…Dityrosine bonds have been found in only one membrane protein, the angiotensin II AT2 receptor [15]. Dityrosine bond formation increases with aging, cellular stress, UV and γ irradiation and disease [16], [17]. Increased levels of dityrosine modified proteins have been found in lesions such as atheromatous plates [18] and cataracts [16]; in pathological processes such as acute inflammation and systemic bacterial infection [19].…”

Section: Introductionmentioning

confidence: 99%

SLC30A3 (ZnT3) Oligomerization by Dityrosine Bonds Regulates Its Subcellular Localization and Metal Transport Capacity

et al. 2009

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Non-covalent and covalent homo-oligomerization of membrane proteins regulates their subcellular localization and function. Here, we described a novel oligomerization mechanism affecting solute carrier family 30 member 3/zinc transporter 3 (SLC30A3/ZnT3). Oligomerization was mediated by intermolecular covalent dityrosine bonds. Using mutagenized ZnT3 expressed in PC12 cells, we identified two critical tyrosine residues necessary for dityrosine-mediated ZnT3 oligomerization. ZnT3 carrying the Y372F mutation prevented ZnT3 oligomerization, decreased ZnT3 targeting to synaptic-like microvesicles (SLMVs), and decreased resistance to zinc toxicity. Strikingly, ZnT3 harboring the Y357F mutation behaved as a “gain-of-function” mutant as it displayed increased ZnT3 oligomerization, targeting to SLMVs, and increased resistance to zinc toxicity. Single and double tyrosine ZnT3 mutants indicate that the predominant dimeric species is formed between tyrosine 357 and 372. ZnT3 tyrosine dimerization was detected under normal conditions and it was enhanced by oxidative stress. Covalent species were also detected in other SLC30A zinc transporters localized in different subcellular compartments. These results indicate that covalent tyrosine dimerization of a SLC30A family member modulates its subcellular localization and zinc transport capacity. We propose that dityrosine-dependent membrane protein oligomerization may regulate the function of diverse membrane protein in normal and disease states.

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“…Dityrosine cross-links are found naturally in numerous structural elements, including insect cuticle protein and elastic ligaments, the chorion layer of mature mosquito eggs, bacterial spores, yeast ascospore and fungal cell walls, worm cuticle and silk proteins, sea mussel adhesive disks, and the fertilization envelope of the sea urchin egg (Anderson, 1964;Raven, Earland, & Little, 1971;Foerder & Shapiro, 1977;De Vore & Gruebel, 1978;Pandey & Aronson, 1979;Briza et al, 1986Briza et al, , 1990Fetterer & Rhoads, 1990;Fetterer, Rhoads, & Urban, 1993;Smail et al, 1995;Li, Hodgeman, & Christensen, 1996). Dityrosine cross-links may contribute to the elasticity and integrity of such mammalian proteins as elastin, collagen, thyroglobulin, human lens protein, and wool keratin (LaBella et al, 1967;LaBella, Waykole, & Queen, 1968;García-Castiñeiras, Dillon, & Spector, 1978;Herzog, Berendorfer, & Saber, 1992;Wells-Knecht et al, 1993;Stewart et al, 1997). Recently, dityrosine has been described in wheat flour as a stabilizing cross-link in the gluten structure (Hanft & Koehler, 2005).…”

mentioning

confidence: 95%

Current analytical methods for the detection of dityrosine, a biomarker of oxidative stress, in biological samples

DiMarco

Giulivi

2006

Mass Spectrometry Reviews

123

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Dityrosine is a fluorescent molecule formed as a result of normal posttranslational processing. In many structural proteins, dityrosine confers resistance to proteolysis and physicochemical trauma as a stabilizing crosslink. Dityrosine has also been found in oxidative/nitrative stress under a variety of conditions and biological systems. In this regard, it has been used as an important biomarker for oxidatively modified proteins during UV and gamma-irradiation, aging, and exposure to oxygen free radicals, nitrogen dioxide, peroxynitrite, and lipid hydroperoxides. Renewed interest in dityrosine and other tyrosine oxidation products as clinical indicators of oxidative modification has driven the development of important techniques for the specific analysis and quantification of these molecules. The presence of elevated levels of dityrosine in mammalian tissue and urine samples has been measured by chromatographic separation followed by mass spectrometry GC-MS and HPLC-MS/MS. Increases in dityrosine levels have been associated with pathologies such as eye cataracts, atherosclerosis, acute inflammation, and Alzheimer's disease. The continued development of, and increased accessibility to, improved mass spectrometric instrumentation will expand the capability, feasibility, and sensitivity with which specific biomarkers like dityrosine can be measured.

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Detection of Bityrosine in Cataractous Human Lens Protein

Cited by 66 publications

References 15 publications

Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins.

Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins.

SLC30A3 (ZnT3) Oligomerization by Dityrosine Bonds Regulates Its Subcellular Localization and Metal Transport Capacity

Current analytical methods for the detection of dityrosine, a biomarker of oxidative stress, in biological samples

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