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Chemical Compound Review

Bityrosine     2-amino-3-[3-[5-(2-amino-2- carboxy-ethyl)...

Synonyms: o,o-Dityrosine, AGN-PC-001SOU, SureCN338068, AG-H-98607, CHEBI:50607, ...
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Disease relevance of Bityrosine

  • Increases in dityrosine levels have been associated with pathologies such as eye cataracts, atherosclerosis, acute inflammation, and Alzheimer's disease [1].
  • Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation [2].
  • Dityrosine was detected in the coronary effluent of hearts infused with synthetic ONOO-. In hearts subjected to 20 min of global, no-flow ischemia there was a marked rise in endogenous ONOO- formation which peaked at 30 s of reperfusion [3].
  • Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry [4].
  • A recombinant fragment of CUT-2, produced in E. coli, can be cross-linked in vitro by horse radish peroxidase via dityrosine formation to give large molecular species [1] [5].

High impact information on Bityrosine

  • To analyze the mechanism of assembly of the fertilization membrane of the sea urchin Strongylocentrotus purpuratus, we inhibited the ovoperoxidase that catalyzes dityrosine formation to isolate an uncrosslinked, soft fertilization membrane (SFM) [6].
  • As the DIT2 gene product has significant homology with cytochrome P-450s, DIT2 may be responsible for catalyzing the oxidation of tyrosine residues in the formation of dityrosine [7].
  • Taking advantage of the natural fluorescence imparted to yeast spores by the presence of a dityrosine-containing macromolecule in the spore wall, we identified and cloned two genes, termed DIT1 and DIT2, which are required for spore wall maturation [7].
  • We speculate that protein dityrosine cross-linking by myeloperoxidase may play a role in bacterial killing or injuring normal tissue [8].
  • Activated neutrophils likewise converted polypeptide tyrosines to dityrosine [8].

Chemical compound and disease context of Bityrosine


Biological context of Bityrosine

  • DIT2, which is a member of the cytochrome P450 superfamily, is responsible for the dimerization reaction leading to the dityrosine-containing precursors [11].
  • Although homozygous tep1 mutants initiate the meiotic program and form spores with wild-type kinetics, analysis of the spores produced in tep1 mutants indicates a specific defect in the trafficking or deposition of dityrosine, a major component of yeast spore walls, to the surface [12].
  • Current analytical methods for the detection of dityrosine, a biomarker of oxidative stress, in biological samples [1].
  • Although the proteins (peptides) of the spore wall are insoluble, the macromolecule containing dityrosine can be solubilized by partial acid hydrolysis of spore walls [13].
  • Both AOPP-HSA and AGE-HSA, but not purified dityrosine, were capable of triggering the oxidative burst of human monocytes in cultures [14].

Anatomical context of Bityrosine

  • At fertilization, the glycocalyx (vitelline layer) of the sea urchin egg is transformed into an elevated fertilization envelope by the association of secreted peptides and the formation of intermolecular dityrosine bonds [15].
  • The requirement for H2O2 and the inhibition by heme poisons suggest that activated phagocytes synthesize dityrosine by a peroxidative mechanism [16].
  • Aedes aegypti chorion peroxidase (CPO) plays a crucial role in chorion hardening by catalyzing chorion protein cross-linking through dityrosine formation [17].
  • Comparable results, in terms of dityrosine release, were obtained using red blood cells of different sources after exposing them to a flux of H(2)O(2) [18].
  • Ovoperoxidase, the enzyme that catalyzes the dityrosine cross-linking of fertilization membranes of eggs from the sea urchin Stronglyocentrotus purpuratus, exhibits slow changes in catalytic activity upon alterations of pH, with attendant changes in spectral properties [19].

Associations of Bityrosine with other chemical compounds


Gene context of Bityrosine

  • The role of dityrosine formation in the crosslinking of CUT-2, the product of a second cuticlin gene of Caenorhabditis elegans [23].
  • Regarding the colloidal insoluble multimerized Tg (m-Tg), which bears dityrosine bridges and is present in the follicular lumen, a mild oxidative system generated different soluble forms of Tg, more or less compacted by hydrophobic associations, and linked with Grp78 and Grp94 [24].
  • Blood samples were drawn pre-HD, pre-IVIR, and post-IVIR for iron, transferrin, TNF-alpha, AOPP, thiol, total antioxidant capacity (TEAC), and dityrosine levels and pre-HD for ferritin and CRP levels [25].
  • Previous studies have shown that exposure to oxidative and nitrative species stabilizes alpha-synuclein filaments in vitro, and this stabilization may be due to dityrosine cross-linking [26].
  • The same conclusion was reached independently by an investigation of spores of a strain homozygous for the mutation gcn1, which lack the outermost layers of the spore wall and were practically devoid of dityrosine [27].

Analytical, diagnostic and therapeutic context of Bityrosine


  1. Current analytical methods for the detection of dityrosine, a biomarker of oxidative stress, in biological samples. Dimarco, T., Giulivi, C. Mass spectrometry reviews (2007) [Pubmed]
  2. Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge. Smith, D.P., Smith, D.G., Curtain, C.C., Boas, J.F., Pilbrow, J.R., Ciccotosto, G.D., Lau, T.L., Tew, D.J., Perez, K., Wade, J.D., Bush, A.I., Drew, S.C., Separovic, F., Masters, C.L., Cappai, R., Barnham, K.J. J. Biol. Chem. (2006) [Pubmed]
  3. Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Yasmin, W., Strynadka, K.D., Schulz, R. Cardiovasc. Res. (1997) [Pubmed]
  4. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Shishehbor, M.H., Brennan, M.L., Aviles, R.J., Fu, X., Penn, M.S., Sprecher, D.L., Hazen, S.L. Circulation (2003) [Pubmed]
  5. Assembly of nematode cuticle: role of hydrophobic interactions in CUT-2 cross-linking. Parise, G., Bazzicalupo, P. Biochim. Biophys. Acta (1997) [Pubmed]
  6. Assembly of the fertilization membrane of the sea urchin: isolation of a divalent cation-dependent intermediate and its crosslinking in vitro. Kay, E., Eddy, E.M., Shapiro, B.M. Cell (1982) [Pubmed]
  7. Isolation of two developmentally regulated genes involved in spore wall maturation in Saccharomyces cerevisiae. Briza, P., Breitenbach, M., Ellinger, A., Segall, J. Genes Dev. (1990) [Pubmed]
  8. Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins. Heinecke, J.W., Li, W., Francis, G.A., Goldstein, J.A. J. Clin. Invest. (1993) [Pubmed]
  9. Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer's disease. Reynolds, M.R., Berry, R.W., Binder, L.I. Biochemistry (2005) [Pubmed]
  10. Characterisation of photo-oxidation products within photoyellowed wool proteins: tryptophan and tyrosine derived chromophores. Dyer, J.M., Bringans, S.D., Bryson, W.G. Photochem. Photobiol. Sci. (2006) [Pubmed]
  11. The sporulation-specific enzymes encoded by the DIT1 and DIT2 genes catalyze a two-step reaction leading to a soluble LL-dityrosine-containing precursor of the yeast spore wall. Briza, P., Eckerstorfer, M., Breitenbach, M. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  12. TEP1, the yeast homolog of the human tumor suppressor gene PTEN/MMAC1/TEP1, is linked to the phosphatidylinositol pathway and plays a role in the developmental process of sporulation. Heymont, J., Berenfeld, L., Collins, J., Kaganovich, A., Maynes, B., Moulin, A., Ratskovskaya, I., Poon, P.P., Johnston, G.C., Kamenetsky, M., DeSilva, J., Sun, H., Petsko, G.A., Engebrecht, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  13. Characterization of a DL-dityrosine-containing macromolecule from yeast ascospore walls. Briza, P., Ellinger, A., Winkler, G., Breitenbach, M. J. Biol. Chem. (1990) [Pubmed]
  14. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. Witko-Sarsat, V., Friedlander, M., Nguyen Khoa, T., Capeillère-Blandin, C., Nguyen, A.T., Canteloup, S., Dayer, J.M., Jungers, P., Drüeke, T., Descamps-Latscha, B. J. Immunol. (1998) [Pubmed]
  15. Regulation of extracellular matrix assembly: in vitro reconstitution of a partial fertilization envelope from isolated components. Weidman, P.J., Shapiro, B.M. J. Cell Biol. (1987) [Pubmed]
  16. Dityrosine, a specific marker of oxidation, is synthesized by the myeloperoxidase-hydrogen peroxide system of human neutrophils and macrophages. Heinecke, J.W., Li, W., Daehnke, H.L., Goldstein, J.A. J. Biol. Chem. (1993) [Pubmed]
  17. Novel glycosidic linkage in Aedes aegypti chorion peroxidase: N-mannosyl tryptophan. Li, J.S., Cui, L., Rock, D.L., Li, J. J. Biol. Chem. (2005) [Pubmed]
  18. Mechanism of the formation and proteolytic release of H2O2-induced dityrosine and tyrosine oxidation products in hemoglobin and red blood cells. Giulivi, C., Davies, K.J. J. Biol. Chem. (2001) [Pubmed]
  19. pH-induced hysteretic transitions of ovoperoxidase. Deits, T., Shapiro, B.M. J. Biol. Chem. (1985) [Pubmed]
  20. In vitro effects of oxygen-derived free radicals on type I and type II cAMP-dependent protein kinases. Dimon-Gadal, S., Gerbaud, P., Keryer, G., Anderson, W., Evain-Brion, D., Raynaud, F. J. Biol. Chem. (1998) [Pubmed]
  21. Human phagocytes employ the myeloperoxidase-hydrogen peroxide system to synthesize dityrosine, trityrosine, pulcherosine, and isodityrosine by a tyrosyl radical-dependent pathway. Jacob, J.S., Cistola, D.P., Hsu, F.F., Muzaffar, S., Mueller, D.M., Hazen, S.L., Heinecke, J.W. J. Biol. Chem. (1996) [Pubmed]
  22. The role of cysteine residues in the oxidation of ferritin. Welch, K.D., Reilly, C.A., Aust, S.D. Free Radic. Biol. Med. (2002) [Pubmed]
  23. The role of dityrosine formation in the crosslinking of CUT-2, the product of a second cuticlin gene of Caenorhabditis elegans. Lassandro, F., Sebastiano, M., Zei, F., Bazzicalupo, P. Mol. Biochem. Parasitol. (1994) [Pubmed]
  24. Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen. Delom, F., Lejeune, P.J., Vinet, L., Carayon, P., Mallet, B. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  25. Induction of protein oxidation by intravenous iron in hemodialysis patients: role of inflammation. Tovbin, D., Mazor, D., Vorobiov, M., Chaimovitz, C., Meyerstein, N. Am. J. Kidney Dis. (2002) [Pubmed]
  26. Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. Norris, E.H., Giasson, B.I., Ischiropoulos, H., Lee, V.M. J. Biol. Chem. (2003) [Pubmed]
  27. Dityrosine is a prominent component of the yeast ascospore wall. A proof of its structure. Briza, P., Winkler, G., Kalchhauser, H., Breitenbach, M. J. Biol. Chem. (1986) [Pubmed]
  28. Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. Zhang, R., Brennan, M.L., Shen, Z., MacPherson, J.C., Schmitt, D., Molenda, C.E., Hazen, S.L. J. Biol. Chem. (2002) [Pubmed]
  29. Vitamin C prevents cigarette smoke-induced oxidative damage in vivo. Panda, K., Chattopadhyay, R., Chattopadhyay, D.J., Chatterjee, I.B. Free Radic. Biol. Med. (2000) [Pubmed]
  30. Candida albicans cell walls contain the fluorescent cross-linking amino acid dityrosine. Smail, E.H., Briza, P., Panagos, A., Berenfeld, L. Infect. Immun. (1995) [Pubmed]
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