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Gene Review

Tyr  -  tyrosinase

Mus musculus

Synonyms: Albino locus protein, Monophenol monooxygenase, Oca1, Tyrosinase, albino, ...
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Disease relevance of Tyr


Psychiatry related information on Tyr

  • Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation [6].
  • The preimplantation and early postimplantation effect of chronic alcohol consumption (at least a month before mating and during pregnancy until killing) and of acute ethanol intoxication during the preimplantation period (i.v. injection of ethanol) was studied on albino rats (Wistar) and albino mice (RAP) [7].
  • In albino mammals, lack of pigment in the retinal pigment epithelium is associated with retinal defects, including poor visual acuity from a photoreceptor deficit in the central retina and poor depth perception from a decrease in ipsilaterally projecting retinal fibers [8].
  • Immunization with peptide analogues revealed that substitution of Tyr for Phe94 was compatible with Id-lambda 2(315) mimicry, but substitution of Ser for Arg95 or Thr for Asn96 destroyed the Th-recognized Id [9].
  • Comparison of kcat in catalysis by Lys 91 and Tyr 131 and the corresponding double mutant showed a strong antagonistic interaction between these sites, suggesting a cooperative behavior in facilitating the proton-transfer step of catalysis [10].

High impact information on Tyr

  • Differentiation antigens coded by genes such as tyrosinase are also recognized on human melanoma by autologous CTL [11].
  • IFN-alpha/beta receptor is physically associated with the cytoplasmic Tyr kinase JAK1, hence, in addition to ligand binding, it is directly involved in signal transduction [12].
  • A highly active competitor peptide analog was synthesized in which Tyr was separated from the Thr-Leu pair by a pentaproline spacer [13].
  • These results suggest that two events must occur to activate the full transforming potential of pp60c-src: hypophosphorylation at Tyr 527 and hyperphosphorylation at Tyr 416 [14].
  • Modifying Tyr 416 to phenylalanine in the 527 or the 519/527 mutants only partially inhibited their kinase activities yet abolished their ability to induce focus formation and promote growth in soft agar [14].

Chemical compound and disease context of Tyr

  • Since, so far no effective therapeutic is available for the treatment of pancreatic cancer patients, we have examined the therapeutic potential of either FK228, the combination of these two Tyr-kinase inhibitors or GL-2003, a water-soluble derivative of AG 879, on human pancreatic cancer (Capan-1) xenograft in mice [15].
  • Melanogenesis is regulated in large part by tyrosinase (monophenol monooxygenase; monophenol, L-dopa:oxygen oxidoreductase, EC, and defective tyrosinase leads to albinism [16].
  • In melanocytes and in melanoma cells, cyclic AMP (cAMP)-elevating agents stimulate melanogenesis and increase the transcription of tyrosinase, the rate-limiting enzyme in melanin synthesis [17].
  • Tyrosinase, the primary enzyme in melanin synthesis commonly mutated in albinism, oxidizes l-tyrosine to l-dopaquinone using l-3,4-dihydroxyphenylalanine (L-DOPA) as an intermediate product [18].
  • The level of mouse tyrosinase mRNA was elevated after stimulation of Cloudman S-91 melanoma cells with melanotropin and isobutylmethylxanthine and the level of transcript reflected that of tyrosinase activity and melanin content in the cells [19].

Biological context of Tyr

  • No difference in diabetes development was observed in Tyr/Tyr(c) heterozygotes, showing that protection was recessive [20].
  • Mice homozygous for specific deletions around the albino locus on chromosome 7 die within the first few hours of birth [2].
  • Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice [21].
  • We find that c14CoS homozygotes which express transgenic Fah are complemented for all aspects of the complex lethal albino phenotype [2].
  • Transient expression assays showed that TDE confers efficient expression of a firefly luciferase reporter gene linked to the tyrosinase gene promoter in MeWo pigmented melanoma cells but not in HeLa cells, which do not express tyrosinase [22].

Anatomical context of Tyr

  • Pulse/chase labeling experiments show that Tyr is degraded more quickly in Tyrp1(b) mutant melanocytes than in melanocytes wild type at that locus [23].
  • We have recently shown that mouse melanosomes contain two electrophoretically distinct tyrosinase isoenzymes, termed low electrophoretic mobility tyrosinase (LEMT) and high electrophoretic mobility tyrosinase (HEMT), that can be resolved and purified [24].
  • A large number of mutations have been identified in tyrosinase, with many leading to its misfolding, endoplasmic reticulum (ER) retention, and degradation [25].
  • Here we describe the folding and maturation of human tyrosinase (TYR) using an in vitro translation system coupled with ER-derived microsomes or with semipermeabilized cells, as an intact ER source [25].
  • Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles [4].

Associations of Tyr with chemical compounds


Physical interactions of Tyr

  • In sum, these results suggest that, in addition to its catalytic function in oxidizing DHICA, Tyrp1 may play an important role in stabilizing Tyr, a second potential role in the regulation of melanin formation [23].
  • Physical mapping of the albino-deletion complex in the mouse to localize alf/hsdr-1, a locus required for neonatal survival [31].
  • These results suggest that melanoma cells possess spare melanotropin receptors and that [Nle4, D-Phe7]-substituted analogues bind almost irreversibly to these receptors or to some other component of the adenylate cyclase enzyme complex responsible for enhancing tyrosinase activity and melanin production [32].

Enzymatic interactions of Tyr


Regulatory relationships of Tyr

  • TRP-1 and tyrosinase probes also detected melanoblasts but were both expressed later in development than TRP-2 [36].
  • Our results show that TGF-beta1 significantly inhibits melanin synthesis in a concentration-dependent manner and that it reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme [37].
  • Alpha-MSH-induced tyrosinase activation and melanin production were completely inhibited by a 100-fold higher concentration of AP9 l -131; the IC50 values for AP91-131 in thetwo assay systems were 91 +/- 22 nM and 95 +/- 15 nM respectively [38].
  • TRP-1 was induced simultaneously with tyrosinase, although its inducibility was lower than that of tyrosinase [39].
  • Using two ODNs we corrected an inactivating mutation in the tyrosinase gene and introduced an activating mutation into the c-kit gene in a single albino mouse melanocyte [40].

Other interactions of Tyr

  • Mice homozygous for albino deletions encompassing the locus alf/hsdr-1 die shortly after birth [21].
  • Recently, we and others showed that the gene for fumarylacetoacetate hydrolase (Fah), an enzyme involved in tyrosine catabolism, was disrupted by the lethal albino deletion c14CoS [2].
  • Although the brown locus, encoding TRP1, was actually the first member of the tyrosinase gene family to be cloned, its catalytic function (which results in the production of black rather than brown melanin) has been in general dispute [41].
  • Several genes critical to the enzymatic regulation of melanin production in mammals have recently been cloned and mapped to the albino, brown and slaty loci in mice [41].
  • Deletion mutations at the albino (c) locus have been useful for continuing the development of fine-structure physical and functional maps of the Fes-Hbb region of mouse chromosome 7 [42].

Analytical, diagnostic and therapeutic context of Tyr


  1. The ocular albinism type 1 (OA1) gene controls melanosome maturation and size. Cortese, K., Giordano, F., Surace, E.M., Venturi, C., Ballabio, A., Tacchetti, C., Marigo, V. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  2. Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1. Kelsey, G., Ruppert, S., Beermann, F., Grund, C., Tanguay, R.M., Schütz, G. Genes Dev. (1993) [Pubmed]
  3. Changes in expression of putative antigens encoded by pigment genes in mouse melanomas at different stages of malignant progression. Orlow, S.J., Hearing, V.J., Sakai, C., Urabe, K., Zhou, B.K., Silvers, W.K., Mintz, B. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  4. Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4. Costin, G.E., Valencia, J.C., Vieira, W.D., Lamoreux, M.L., Hearing, V.J. J. Cell. Sci. (2003) [Pubmed]
  5. Establishment and partial characterization of SV40 virus-immortalized hepatocyte lines of normal and lethal mutant mice carrying a deletion on chromosome 7. Paul, D., Kwon, B.S., Höhne, M., Tönjes, R., Haq, A.K., Hoffmann, B. J. Cell. Physiol. (1989) [Pubmed]
  6. Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation. Wang, R., Tang, P., Wang, P., Boissy, R.E., Zheng, H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. The effect of ethanol upon early development in mice and rats. I. In vivo effect upon preimplantation and early postimplantation stages. Sandor, S., Checiu, M., Fazakas-Todea, I., Gârban, Z. Morphologie et embryologie. (1980) [Pubmed]
  8. Spatiotemporal features of early neuronogenesis differ in wild-type and albino mouse retina. Rachel, R.A., Dolen, G., Hayes, N.L., Lu, A., Erskine, L., Nowakowski, R.S., Mason, C.A. J. Neurosci. (2002) [Pubmed]
  9. The T lymphocyte response to syngeneic lambda 2 light chain idiotopes. Significance of individual amino acids revealed by variant lambda 2 chains and idiotope-mimicking chemically synthesized peptides. Hannestad, K., Kristoffersen, G., Briand, J.P. Eur. J. Immunol. (1986) [Pubmed]
  10. Intramolecular proton transfer from multiple sites in catalysis by murine carbonic anhydrase V. Earnhardt, J.N., Qian, M., Tu, C., Laipis, P.J., Silverman, D.N. Biochemistry (1998) [Pubmed]
  11. Tumor antigens recognized by T lymphocytes. Boon, T., Cerottini, J.C., Van den Eynde, B., van der Bruggen, P., Van Pel, A. Annu. Rev. Immunol. (1994) [Pubmed]
  12. The human interferon alpha/beta receptor: characterization and molecular cloning. Novick, D., Cohen, B., Rubinstein, M. Cell (1994) [Pubmed]
  13. Competitor analogs for defined T cell antigens: peptides incorporating a putative binding motif and polyproline or polyglycine spacers. Maryanski, J.L., Verdini, A.S., Weber, P.C., Salemme, F.R., Corradin, G. Cell (1990) [Pubmed]
  14. Tyrosine phosphorylation regulates the biochemical and biological properties of pp60c-src. Piwnica-Worms, H., Saunders, K.B., Roberts, T.M., Smith, A.E., Cheng, S.H. Cell (1987) [Pubmed]
  15. Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Hirokawa, Y., Levitzki, A., Lessene, G., Baell, J., Xiao, Y., Zhu, H., Maruta, H. Cancer Lett. (2007) [Pubmed]
  16. Murine and human b locus pigmentation genes encode a glycoprotein (gp75) with catalase activity. Halaban, R., Moellmann, G. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  17. Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia. Bertolotto, C., Buscà, R., Abbe, P., Bille, K., Aberdam, E., Ortonne, J.P., Ballotti, R. Mol. Cell. Biol. (1998) [Pubmed]
  18. Ectopic expression of tyrosine hydroxylase in the pigmented epithelium rescues the retinal abnormalities and visual function common in albinos in the absence of melanin. Lavado, A., Jeffery, G., Tovar, V., de la Villa, P., Montoliu, L. J. Neurochem. (2006) [Pubmed]
  19. Sequence analysis of mouse tyrosinase cDNA and the effect of melanotropin on its gene expression. Kwon, B.S., Wakulchik, M., Haq, A.K., Halaban, R., Kestler, D. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
  20. "Agouti NOD": identification of a CBA-derived Idd locus on Chromosome 7 and its use for chimera production with NOD embryonic stem cells. Chen, J., Reifsnyder, P.C., Scheuplein, F., Schott, W.H., Mileikovsky, M., Soodeen-Karamath, S., Nagy, A., Dosch, M.H., Ellis, J., Koch-Nolte, F., Leiter, E.H. Mamm. Genome (2005) [Pubmed]
  21. Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice. Ruppert, S., Kelsey, G., Schedl, A., Schmid, E., Thies, E., Schütz, G. Genes Dev. (1992) [Pubmed]
  22. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Yasumoto, K., Yokoyama, K., Shibata, K., Tomita, Y., Shibahara, S. Mol. Cell. Biol. (1994) [Pubmed]
  23. Tyrosinase stabilization by Tyrp1 (the brown locus protein). Kobayashi, T., Imokawa, G., Bennett, D.C., Hearing, V.J. J. Biol. Chem. (1998) [Pubmed]
  24. A new enzymatic function in the melanogenic pathway. The 5,6-dihydroxyindole-2-carboxylic acid oxidase activity of tyrosinase-related protein-1 (TRP1). Jiménez-Cervantes, C., Solano, F., Kobayashi, T., Urabe, K., Hearing, V.J., Lozano, J.A., García-Borrón, J.C. J. Biol. Chem. (1994) [Pubmed]
  25. Tyrosinase maturation and oligomerization in the endoplasmic reticulum require a melanocyte-specific factor. Francis, E., Wang, N., Parag, H., Halaban, R., Hebert, D.N. J. Biol. Chem. (2003) [Pubmed]
  26. Coupling and uncoupling of tumor immunity and autoimmunity. Bowne, W.B., Srinivasan, R., Wolchok, J.D., Hawkins, W.G., Blachere, N.E., Dyall, R., Lewis, J.J., Houghton, A.N. J. Exp. Med. (1999) [Pubmed]
  27. A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase. Tsukamoto, K., Jackson, I.J., Urabe, K., Montague, P.M., Hearing, V.J. EMBO J. (1992) [Pubmed]
  28. Transforming growth factor-beta1 inhibits basal melanogenesis in B16/F10 mouse melanoma cells by increasing the rate of degradation of tyrosinase and tyrosinase-related protein-1. Martínez-Esparza, M., Jiménez-Cervantes, C., Beermann, F., Aparicio, P., Lozano, J.A., García-Borrón, J.C. J. Biol. Chem. (1997) [Pubmed]
  29. The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type. Zdarsky, E., Favor, J., Jackson, I.J. Genetics (1990) [Pubmed]
  30. Production of POMC, CRH-R1, MC1, and MC2 receptor mRNA and expression of tyrosinase gene in relation to hair cycle and dexamethasone treatment in the C57BL/6 mouse skin. Ermak, G., Slominski, A. J. Invest. Dermatol. (1997) [Pubmed]
  31. Physical mapping of the albino-deletion complex in the mouse to localize alf/hsdr-1, a locus required for neonatal survival. Kelsey, G., Schedl, A., Ruppert, S., Niswander, L., Magnuson, T., Klebig, M.L., Rinchik, E.M., Schütz, G. Genomics (1992) [Pubmed]
  32. Prolonged stimulation of S91 melanoma tyrosinase by [Nle4, D-Phe7]-substituted alpha-melanotropins. Abdel Malek, Z.A., Kreutzfeld, K.L., Marwan, M.M., Hadley, M.E., Hruby, V.J., Wilkes, B.C. Cancer Res. (1985) [Pubmed]
  33. Mechanistic inferences from the crystal structure of fumarylacetoacetate hydrolase with a bound phosphorus-based inhibitor. Bateman, R.L., Bhanumoorthy, P., Witte, J.F., McClard, R.W., Grompe, M., Timm, D.E. J. Biol. Chem. (2001) [Pubmed]
  34. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Kim, S., Koga, T., Isobe, M., Kern, B.E., Yokochi, T., Chin, Y.E., Karsenty, G., Taniguchi, T., Takayanagi, H. Genes Dev. (2003) [Pubmed]
  35. Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines. Alessi, D.R., Gomez, N., Moorhead, G., Lewis, T., Keyse, S.M., Cohen, P. Curr. Biol. (1995) [Pubmed]
  36. TRP-2/DT, a new early melanoblast marker, shows that steel growth factor (c-kit ligand) is a survival factor. Steel, K.P., Davidson, D.R., Jackson, I.J. Development (1992) [Pubmed]
  37. Transforming growth factor-beta1 decreases melanin synthesis via delayed extracellular signal-regulated kinase activation. Kim, D.S., Park, S.H., Park, K.C. Int. J. Biochem. Cell Biol. (2004) [Pubmed]
  38. Antagonist and agonist activities of the mouse agouti protein fragment (91-131) at the melanocortin-1 receptor. Eberle, A.N., Bódi, J., Orosz, G., Süli-Vargha, H., Jäggin, V., Zumsteg, U. J. Recept. Signal Transduct. Res. (2001) [Pubmed]
  39. Eumelanin biosynthesis is regulated by coordinate expression of tyrosinase and tyrosinase-related protein-1 genes. Kuzumaki, T., Matsuda, A., Wakamatsu, K., Ito, S., Ishikawa, K. Exp. Cell Res. (1993) [Pubmed]
  40. Simultaneous targeted alteration of the tyrosinase and c-kit genes by single-stranded oligonucleotides. Alexeev, V., Igoucheva, O., Yoon, K. Gene Ther. (2002) [Pubmed]
  41. Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis. Kobayashi, T., Urabe, K., Winder, A., Jiménez-Cervantes, C., Imokawa, G., Brewington, T., Solano, F., García-Borrón, J.C., Hearing, V.J. EMBO J. (1994) [Pubmed]
  42. Molecular analysis of radiation-induced albino (c)-locus mutations that cause death at preimplantation stages of development. Rinchik, E.M., Tönjes, R.R., Paul, D., Potter, M.D. Genetics (1993) [Pubmed]
  43. Stimulation of melanogenesis by tetradecanoylphorbol 13-acetate (TPA) in mouse melanocytes and neural crest cells. Prince, S., Wiggins, T., Hulley, P.A., Kidson, S.H. Pigment Cell Res. (2003) [Pubmed]
  44. Inhibitors of mammalian melanocyte tyrosinase: in vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors. Curto, E.V., Kwong, C., Hermersdörfer, H., Glatt, H., Santis, C., Virador, V., Hearing, V.J., Dooley, T.P. Biochem. Pharmacol. (1999) [Pubmed]
  45. Molecular interactions within the melanogenic complex: formation of heterodimers of tyrosinase and TRP1 from B16 mouse melanoma. Jiménez-Cervantes, C., Martínez-Esparza, M., Solano, F., Lozano, J.A., García-Borrón, J.C. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
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