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| | Schematic of Tyrosinase Polypeptide adapted from Mashima 1994. SP (signal peptide), EGF (Epidermal growth factor)-like domain, CuA and CuB (Copper binding domains) and TM (transmembrane domain). |
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| Description | 529 amino acids; nascent protein is 60 kDa; Posttranslationally modified by glycosylation giving an 80 kDa protein. Contains an 18 amino acid long signal peptide, six N glycosylation sites, two copper binding sites (CuA and CuB) and a transmembrane domain (Mashima, 1994; Kosmadaki et al., 2010). |
| Expression | Expressed mainly in neural crest derived melanocytes and is sorted into the melanosomes within the melanocyte. Tyrosinase is also found in retinal pigment epithelium cells (Hearing, 2011). |
| Localisation | Transmembrane protein. |
| Function | Tyrosinase catalyzes conversion of tyrosine to DOPA; the rate limiting step of melanin biosynthesis and subsequently DOPA to dopaquinone (Olivares et al., 2009). |
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| | Tyrosinase catalyzes the conversion of tyrosine to DOPA in the rate-limiting step of melanin biosynthesis. |
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| Homology | The protein tyrosinase related protein 1 (TRP1) is a member of the tyrosinase protein family and utilizes copper as its cofactor. Its function in humans is not well elucidated but is thought to aid in maintaining tyrosinase catalytic activity and stability. It is also involved in maintaining melanosome structure as well as proliferation and cell death of melanocytes (Sarangarajan et al., 2000; Ghanem et al., 2011). Tyrosinase related protein 2 (TRP2), which is also known as DOPAchrome tautomerase catalyzes the conversion of DOPAchrome to 5,6-dihydroxy indole-2-carboxylic acid (DHICA). TRP2 binds 2 zinc ions as cofactors instead of copper (Olivares et al., 2001; Wan et al., 2011). |
| Note | |
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| Entity | Melanoma |
| Disease | Highly aggressive neoplasma arising from melanocytes. Melanoma is responsible for the majority of skin cancer related deaths with a very high probability of metastasis. This neoplasm is greatly resistant to most conventional therapies. Due to the longevity of melanocytes, these cells are considered to have a greater mutagenic burden. This burden is also greater due to the position of melanocytes within the skin and their exposure to UV light. Tyrosinase enzymatic activity has been found to be associated with a better prognosis due to its association with functional activity of the tumor supressor p53. Tyrosinase-mediated melanin production signaled by p53 activation is a key protective response to UV damage (Flaherty, 2012; Gilcrest, 2011). |
| Oncogenesis | Several environmental and genetic factors are involved in the complex process of melanocytic tumorigenesis. Melanin production involving tyrosinase as the rate-limiting step has been shown to protect keratinocytes from DNA damage and oxidative stress from ultra violet radiation; A low incidence of melanoma in darker skinned populations has been observed, indicating a photoprotective role of melanin (Kanavy, 2011). |
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| Entity | Oculocutaneous albinism 1A |
| Disease | Autosomal recessive condition that results in partial or complete loss of tyrosinase activity. Complete loss of activity results in the absence of melanin in the skin and eyes and is classified as OCA1A and the presence of only reduced tyrosinase activity is classified as OCA1B. Complete loss of tyrosinase activity results in the total absence of melanin in the skin and hair. The iris in patients with OCA1A is light blue or gray and the retina lacks pigmentation as well. Tyrosinase null patients have greatly reduced visual acuity accompanied by nystagmus, strabismus, and usually photophobia (Ray et al., 2007). Patients with OCA1B present with varying levels of pigment. The hair in these patients is often yellow. The yellow color is a result of the pheomelanin synthesis. Dopaquinone has a high affinity for sulfhydryl compounds and produces pheomelanin as a result, causing yellow pigmentation. Patients with OCA1B often develop pigmentation in the cooler regions of the body, like the extremities (Chiang et al., 2008). |
| Prognosis | Prognosis in patients is generally good with no system abnormalities other than the loss or reduction in pigmentation. Patients are advised to protect their skin from sun to prevent sunburn (Ray et al., 2007). |
| Oncogenesis | Transcription of tyrosinase has been shown to increase with activation of the tumor suppressor p53, linking both to the tanning response following exposure to UV damage (Khlgatian et al., 2002 and Cui et al., 2007). |
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| Determination of variants in the 3'-region of the tyrosinase gene requires locus specific amplification. |
| Chaki M, Mukhopadhyay A, Ray K. |
| Hum Mutat. 2005 Jul;26(1):53-8. |
| PMID 15895460 |
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| A new hypothesis of OCA1B. |
| Chiang PW, Drautz JM, Tsai AC, Spector E, Clericuzio CL. |
| Am J Med Genet A. 2008 Nov 15;146A(22):2968-70. |
| PMID 18925668 |
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| Central role of p53 in the suntan response and pathologic hyperpigmentation. |
| Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE. |
| Cell. 2007 Mar 9;128(5):853-64. |
| PMID 17350573 |
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| Targeting metastatic melanoma. |
| Flaherty KT. |
| Annu Rev Med. 2012;63:171-83. Epub 2011 Oct 27. (REVIEW) |
| PMID 22034865 |
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| Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. |
| Ghanem G, Fabrice J. |
| Mol Oncol. 2011 Apr;5(2):150-5. Epub 2011 Feb 3. (REVIEW) |
| PMID 21324755 |
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| Molecular aspects of tanning. |
| Gilchrest BA. |
| J Invest Dermatol. 2011 Nov 17;131(E1):E14-7. (REVIEW) |
| PMID 22094400 |
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| Determination of melanin synthetic pathways. |
| Hearing VJ. |
| J Invest Dermatol. 2011 Nov 17;131(E1):E8-E11. (REVIEW) |
| PMID 22094404 |
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| Ultraviolet radiation and melanoma. |
| Kanavy HE, Gerstenblith MR. |
| Semin Cutan Med Surg. 2011 Dec;30(4):222-8. (REVIEW) |
| PMID 22123420 |
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| Tyrosinase gene expression is regulated by p53. |
| Khlgatian MK, Hadshiew IM, Asawanonda P, Yaar M, Eller MS, Fujita M, Norris DA, Gilchrest BA. |
| J Invest Dermatol. 2002 Jan;118(1):126-32. |
| PMID 11851885 |
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| Mutation spectrum of the TYR and SLC45A2 genes in patients with oculocutaneous albinism. |
| Ko JM, Yang JA, Jeong SY, Kim HJ. |
| Mol Med Report. 2012 Apr;5(4):943-8. doi: 10.3892/mmr.2012.764. Epub 2012 Jan 25. |
| PMID 22294196 |
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| Recent progresses in understanding pigmentation. |
| Kosmadaki MG, Naif A, Hee-Young P. |
| G Ital Dermatol Venereol. 2010 Feb;145(1):47-55. (REVIEW) |
| PMID 20197745 |
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| Molecular and biological control of melanogenesis through tyrosinase genes and intrinsic and extrinsic regulatory factors. |
| Mishima Y. |
| Pigment Cell Res. 1994 Dec;7(6):376-87. (REVIEW) |
| PMID 7761345 |
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| New insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins. |
| Olivares C, Solano F. |
| Pigment Cell Melanoma Res. 2009 Dec;22(6):750-60. Epub 2009 Sep 7. (REVIEW) |
| PMID 19735457 |
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| Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1. |
| Ray K, Chaki M, Sengupta M. |
| Prog Retin Eye Res. 2007 Jul;26(4):323-58. Epub 2007 Jan 17. (REVIEW) |
| PMID 17355913 |
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| Mutant alleles at the brown locus encoding tyrosinase-related protein-1 (TRP-1) affect proliferation of mouse melanocytes in culture. |
| Sarangarajan R, Zhao Y, Babcock G, Cornelius J, Lamoreux ML, Boissy RE. |
| Pigment Cell Res. 2000 Oct;13(5):337-44. |
| PMID 11041210 |
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| A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase. |
| Tsukamoto K, Jackson IJ, Urabe K, Montague PM, Hearing VJ. |
| EMBO J. 1992 Feb;11(2):519-26. |
| PMID 1537333 |
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| Regulation of melanocyte pivotal transcription factor MITF by some other transcription factors. |
| Wan P, Hu Y, He L. |
| Mol Cell Biochem. 2011 Aug;354(1-2):241-6. Epub 2011 Apr 26. (REVIEW) |
| PMID 21519923 |
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