Tyrosinase

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Tyrosinase
Identifiers
Symbols TYR ; ATN; CMM8; OCA1; OCA1A; OCAIA; SHEP3
External IDs OMIM606933 MGI98880 HomoloGene30969 ChEMBL: 1973 GeneCards: TYR Gene
EC number 1.14.18.1
RNA expression pattern
PBB GE TYR 206630 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7299 22173
Ensembl ENSG00000077498 ENSMUSG00000004651
UniProt P14679 P11344
RefSeq (mRNA) NM_000372 NM_011661
RefSeq (protein) NP_000363 NP_035791
Location (UCSC) Chr 11:
88.91 – 89.03 Mb
Chr 7:
87.43 – 87.49 Mb
PubMed search [1] [2]

In molecular biology, tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. It is mainly involved in two distinct reactions of melanin synthesis; firstly, the hydroxylation of a monophenol and secondly, the conversion of an o-diphenol to the corresponding o-quinone. o-Quinone undergoes several reactions to eventually form melanin.[1] Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from tyrosine by oxidation, as in the blackening of a peeled or sliced potato exposed to air. It is found inside melanosomes which are synthesised in the skin melanocytes. In humans, the tyrosinase enzyme is encoded by the TYR gene.[2]

Clinical significance[edit]

A mutation in the tyrosinase gene resulting in impaired tyrosinase production leads to type I oculocutaneous albinism, a hereditary disorder that affects one in every 17,000 people.[3]

Tyrosinase activity is very important. If uncontrolled during melanoma, it results in increased melanin synthesis.

Several polyphenols, including flavonoids or stilbenoid, substrate analogues, free radical scavengers, and copper chelators, have been known to inhibit tyrosinase.[4] Henceforth, the medical and cosmetic industries are focusing research on tyrosinase inhibitors to treat skin disorders.[1]

Catalyzed reaction[edit]

monophenol monooxygenase
Catechol-Quinone.svg
Catechol-Quinone
Identifiers
EC number 1.14.18.1
CAS number 9002-10-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
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Tyrosinase carries out the oxidation of phenols such as tyrosine and dopamine using dioxygen (O2). In the presence of catechol, benzoquinone is formed (see reaction below). Hydrogens removed from catechol combine with oxygen to form water.

The substrate specificity becomes dramatically restricted in mammalian tyrosinase which uses only L-form of tyrosine or DOPA as substrates, and has restricted requirement for L-DOPA as cofactor.[5]

Structure[edit]

Tyrosinase
PDB 1js8 EBI.jpg
structure of a functional unit from octopus hemocyanin
Identifiers
Symbol Tyrosinase
Pfam PF00264
Pfam clan CL0205
InterPro IPR002227
PROSITE PDOC00398
SCOP 1hc2
SUPERFAMILY 1hc2
Common central domain of tyrosinase
Identifiers
Symbol Tyrosinase
Pfam PF00264
InterPro IPR002227
PROSITE PDOC00398
SCOP 1hc2
SUPERFAMILY 1hc2

Tyrosinases have been isolated and studied from a wide variety of plant, animal, and fungal species. Tyrosinases from different species are diverse in terms of their structural properties, tissue distribution, and cellular location.[6] No common tyrosinase protein structure occurring across all species has been found.[7] The enzymes found in plant, animal, and fungal tissue frequently differ with respect to their primary structure, size, glycosylation pattern, and activation characteristics. However, all tyrosinases have in common a binuclear, type 3 copper centre within their active sites. Here, two copper atoms are each coordinated with three histidine residues.

Transmembrane protein and sorting[edit]

Human tyrosinase is a single membrane-spanning transmembrane protein.[8] In humans, tyrosinase is sorted into melanosomes[9] and the catalytically active domain of the protein resides within melanosomes. Only a small, enzymatically inessential part of the protein extends into the cytoplasm of the melanocyte.

Active site[edit]

Crystallographic structure of a Streptomyces-derived tyrosinase in complex with a so-called "caddie protein"[10] In all models, only the tyrosinase molecule is shown, copper atoms are shown in green and the molecular surface is shown in red. In models D and E, histidine amino acids are shown as a blue line representation. From model E, each copper atom within the active site is indeed complexed with three histidine residues, forming a type 3 copper center. From models C and D, the active site for this protein can be seen to sit within a pillus formed on the molecular surface of the molecule.

The two copper atoms within the active site of tyrosinase enzymes interact with dioxygen to form a highly reactive chemical intermediate that then oxidizes the substrate. The activity of tyrosinase is similar to catechol oxidase, a related class of copper oxidase. Tyrosinases and catechol oxidases are collectively termed polyphenol oxidases.

Gene regulation[edit]

The gene for tyrosinase is regulated by the microphthalmia-associated transcription factor (MITF).[11][12]

References[edit]

  1. ^ a b Kumar CM, Sathisha UV, Dharmesh S, Rao AG, Singh SA (2011). "Interaction of sesamol (3,4-methylenedioxyphenol) with tyrosinase and its effect on melanin synthesis". Biochimie 93 (3): 562–9. doi:10.1016/j.biochi.2010.11.014. PMID 21144881. 
  2. ^ Barton DE, Kwon BS, Francke U (July 1988). "Human tyrosinase gene, mapped to chromosome 11 (q14----q21), defines second region of homology with mouse chromosome 7". Genomics 3 (1): 17–24. doi:10.1016/0888-7543(88)90153-X. PMID 3146546. 
  3. ^ Witkop CJ (October 1979). "Albinism: hematologic-storage disease, susceptibility to skin cancer, and optic neuronal defects shared in all types of oculocutaneous and ocular albinism". Ala J Med Sci 16 (4): 327–30. PMID 546241. 
  4. ^ Chang, Te-Sheng (2009). "An Updated Review of Tyrosinase Inhibitors". International Journal of Molecular Sciences 10 (6): 2440–75. doi:10.3390/ijms10062440. PMC 2705500. PMID 19582213. 
  5. ^ Hearing VJ, Ekel TM, Montague PM, Nicholson JM (February 1980). "Mammalin tyrosinase. Stoichiometry and measurement of reaction products". Biochim. Biophys. Acta 611 (2): 251–68. doi:10.1016/0005-2744(80)90061-3. PMID 6766744. 
  6. ^ Mayer, AM (2006). "Polyphenol oxidases in plants and fungi: Going places? A review". Phytochemistry 67 (21): 2318–2331. doi:10.1016/j.phytochem.2006.08.006. PMID 16973188. 
  7. ^ Jaenicke, E and Decker, H. (2003). "Tyrosinases from crustaceans form hexamers". Biochem. J. 371 (Pt 2): 515–523. doi:10.1042/BJ20021058. PMC 1223273. PMID 12466021. 
  8. ^ Kwon BS, Haq AK, Pomerantz SH, Halaban R (November 1987). "Isolation and sequence of a cDNA clone for human tyrosinase that maps at the mouse c-albino locus". Proc. Natl. Acad. Sci. U.S.A. 84 (21): 7473–7. doi:10.1073/pnas.84.21.7473. PMC 299318. PMID 2823263. 
  9. ^ Theos AC, Tenza D, Martina JA, Hurbain I, Peden AA, Sviderskaya EV, Stewart A, Robinson MS, Bennett DC, Cutler DF, Bonifacino JS, Marks MS, Raposo G (November 2005). "Functions of adaptor protein (AP)-3 and AP-1 in tyrosinase sorting from endosomes to melanosomes". Mol. Biol. Cell 16 (11): 5356–72. doi:10.1091/mbc.E05-07-0626. PMC 1266432. PMID 16162817. 
  10. ^ PDB 1WX3; Matoba Y, Kumagi, T. et al. (2006). "Crystallographic evidence that the dinuclear copper center of tyrosinase is flexible during catalysis". J. Biol. Chem. 281 (13): 8981–8990. doi:10.1074/jbc.M509785200. PMID 16436386. 
  11. ^ Hou L, Panthier JJ, Arnheiter H (2000). "Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF". Development 127 (24): 5379–89. PMID 11076759. 
  12. ^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. 

External links[edit]