関: phenoloxidase、tyrosinase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/07/05 14:34:47」(JST)

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Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme 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.^[2] It is found inside melanosomes which are synthesised in the skin melanocytes. In humans, the tyrosinase enzyme is encoded by the TYR gene.^[3]

Significance

Clinical significance

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 20,000 people.^[4]

Tyrosinase activity is very important. If uncontrolled during melanoma, it results in increased melanin synthesis. Decreasing tyrosinase activity has been targeted for the betterment or prevention of conditions related to the hyperpigmentation of the skin, such as melasma and age spots.^[5]

Several polyphenols, including flavonoids or stilbenoid, substrate analogues, free radical scavengers, and copper chelators, have been known to inhibit tyrosinase.^[6] Henceforth, the medical and cosmetic industries are focusing research on tyrosinase inhibitors to treat skin disorders.^[1]

Significance in food industry

In food industry, tyrosinase inhibition is desired as tyrosinase catalyzes the oxidation of phenolic compounds found in fruits and vegetables into quinones, which gives an undesirable taste and color and also decreases the availability of certain essential amino acids as well as the digestibility of the products. As such, highly effective tyrosinase inhibitors are also needed in agriculture and the food industry.^[7] Well known tyrosinase inhibitors include kojic acid,^[8] tropolone,^[9] coumarins,^[10] vanillic acid, vanillin, and vanillic alcohol.^[11]

Significance in insects

Tyrosinase has a wide range of functions in insects, including wound healing, sclerotization, melanin synthesis and parasite encapsulation. As a result, it is an important enzyme as it is the defensive mechanism of insects. Some insecticides are aimed to inhibit tyrosinase.^[7]

Catalyzed reaction

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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.^[12]

Structure

Tyrosinase

Tridimensional structure of a functional unit from octopus hemocyanin

Identifiers

Symbol

Tyrosinase

Pfam

PF00264

Pfam clan

CL0205

InterPro

IPR002227

PROSITE

PDOC00398

SCOP

1hc2

SUPERFAMILY

1hc2

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Common central domain of tyrosinase

Identifiers

Symbol

Tyrosinase

Pfam

PF00264

InterPro

IPR002227

PROSITE

PDOC00398

SCOP

1hc2

SUPERFAMILY

1hc2

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

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.^[13] No common tyrosinase protein structure occurring across all species has been found.^[14] 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.

Human tyrosinase

Human tyrosinase is a single membrane-spanning transmembrane protein.^[15] In humans, tyrosinase is sorted into melanosomes^[16] 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.

As opposed to fungal tyrosinase, human tyrosinase is a membrane-bound glycoprotein and has 13% carbohydrate content.^[7]

The derived TYR allele (rs2733832) is associated with lighter skin pigmentation in human populations. It is most common in Europe, but is also found at lower, moderate frequencies in Central Asia, the Middle East, North Africa, and among the San and Mbuti Pygmies.^[17]

Active site

Crystallographic structure of a Streptomyces-derived tyrosinase in complex with a so-called "caddie protein"^[18] 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

The gene for tyrosinase is regulated by the microphthalmia-associated transcription factor (MITF).^[19]^[20]

References

^ ^a ^b Kumar CM, Sathisha UV, Dharmesh S, Rao AG, Singh SA (Mar 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.
^ American Heritage Dictionary. Retrieved 2015-03-30.
^ Barton DE, Kwon BS, Francke U (Jul 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.
^ Witkop CJ (Oct 1979). "Albinism: hematologic-storage disease, susceptibility to skin cancer, and optic neuronal defects shared in all types of oculocutaneous and ocular albinism". The Alabama Journal of Medical Sciences 16 (4): 327–30. PMID 546241.
^ Ando H, Kondoh H, Ichihashi M, Hearing VJ (Apr 2007). "Approaches to identify inhibitors of melanin biosynthesis via the quality control of tyrosinase". The Journal of Investigative Dermatology 127 (4): 751–61. doi:10.1038/sj.jid.5700683.
^ Chang TS (Jun 2009). "An updated review of tyrosinase inhibitors". International Journal of Molecular Sciences 10 (6): 2440–75. doi:10.3390/ijms10062440. PMC 2705500. PMID 19582213.
^ ^a ^b ^c Kim YJ, Uyama H (Aug 2005). "Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future". Cellular and Molecular Life Sciences 62 (15): 1707–23. doi:10.1007/s00018-005-5054-y. PMID 15968468.
^ Mendes E, Perry Mde J, Francisco AP (May 2014). "Design and discovery of mushroom tyrosinase inhibitors and their therapeutic applications". Expert Opinion on Drug Discovery 9 (5): 533–54. doi:10.1517/17460441.2014.907789. PMID 24708040.
^ Rescigno A, Sollai F, Pisu B, Rinaldi A, Sanjust E (Aug 2002). "Tyrosinase inhibition: general and applied aspects". Journal of Enzyme Inhibition and Medicinal Chemistry 17 (4): 207–18. doi:10.1080/14756360210000010923. PMID 12530473.
^ Sollai, Francesca; Zucca, Paolo; Sanjust, Enrico; Steri, Daniela; Rescigno, Antonio (2008). "Umbelliferone and Esculetin: Inhibitors or Substrates for Polyphenol Oxidases?". Biological & Pharmaceutical Bulletin 31 (12): 2187–2193. doi:10.1248/bpb.31.2187.
^ Rescigno A, Casañola-Martin GM, Sanjust E, Zucca P, Marrero-Ponce Y (Mar 2011). "Vanilloid derivatives as tyrosinase inhibitors driven by virtual screening-based QSAR models". Drug Testing and Analysis 3 (3): 176–81. doi:10.1002/dta.187. PMID 21125547.
^ Hearing VJ, Ekel TM, Montague PM, Nicholson JM (Feb 1980). "Mammalin tyrosinase. Stoichiometry and measurement of reaction products". Biochimica et Biophysica Acta 611 (2): 251–68. doi:10.1016/0005-2744(80)90061-3. PMID 6766744.
^ Mayer AM (Nov 2006). "Polyphenol oxidases in plants and fungi: going places? A review". Phytochemistry 67 (21): 2318–31. doi:10.1016/j.phytochem.2006.08.006. PMID 16973188.
^ Jaenicke E, Decker H (Apr 2003). "Tyrosinases from crustaceans form hexamers". The Biochemical Journal 371 (Pt 2): 515–23. doi:10.1042/BJ20021058. PMC 1223273. PMID 12466021.
^ Kwon BS, Haq AK, Pomerantz SH, Halaban R (Nov 1987). "Isolation and sequence of a cDNA clone for human tyrosinase that maps at the mouse c-albino locus". Proceedings of the National Academy of Sciences of the United States of America 84 (21): 7473–7. doi:10.1073/pnas.84.21.7473. PMC 299318. PMID 2823263.
^ 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 (Nov 2005). "Functions of adaptor protein (AP)-3 and AP-1 in tyrosinase sorting from endosomes to melanosomes". Molecular Biology of the Cell 16 (11): 5356–72. doi:10.1091/mbc.E05-07-0626. PMC 1266432. PMID 16162817.
^ "Allele Frequency For Polymorphic Site: rs2733832". ALFRED. Retrieved 23 June 2016.
^ PDB: 1WX3; Matoba Y, Kumagai T, Yamamoto A, Yoshitsu H, Sugiyama M (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.
^ Hou L, Panthier JJ, Arnheiter H (Dec 2000). "Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF". Development 127 (24): 5379–89. PMID 11076759.
^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (Dec 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.

External links

GeneReviews/NCBI/NIH/UW entry on Oculocutaneous Albinism Type 1
Tyrosinase at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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3. 微細欠失症候群（12番～22番染色体） microdeletion syndromes chromosomes 12 to 22
4. 銅欠乏性脊髄神経障害 copper deficiency myeloneuropathy

English Journal

Using tyrosinase as a monophenol monooxygenase: A combined strategy for effective inhibition of melanin formation.

Lee SH1,2,3, Baek K4,2,3, Lee JE1,2,3, Kim BG1,4,2,3.
Biotechnology and bioengineering.Biotechnol Bioeng.2015 Oct 13. doi: 10.1002/bit.25855. [Epub ahead of print]
Tyrosinase is a binuclear copper-containing metalloprotein that leads the fast and regio-selective o-hydroxylation of monophenols to o-diphenols. However, the subsequent second oxidation to produce o-quinones, i.e., melanin precursors, from the o-diphenols has restricted its use to the production of
PMID 26461518

Anti-melanogenesis and antigenotoxic activities of eriodictyol in murine melanoma (B16-F10) and primary human keratinocyte cells.

Imen MB1, Chaabane F1, Nadia M1, Soumaya KJ1, Kamel G2, Leila CG3.
Life sciences.Life Sci.2015 Aug 15;135:173-8. doi: 10.1016/j.lfs.2015.06.022. Epub 2015 Jul 2.
AIMS: The objective of this study was to examine the effect of eriodictyol on melanogenesis in cultured murine melanoma cells (B16-F10) and its antigenotoxic and antioxidant potentials on primary human keratinocyte (PHK) cells.MAIN METHODS: Anti-melanogenic effect was performed via the determination
PMID 26141996

Modulation effects of sweroside isolated from the Lonicera japonica on melanin synthesis.

Jeong YT1, Jeong SC1, Hwang JS2, Kim JH3.
Chemico-biological interactions.Chem Biol Interact.2015 Aug 5;238:33-9. doi: 10.1016/j.cbi.2015.05.022. Epub 2015 Jun 5.
In the course of screening for the melanogenesis inhibitors, sweroside was isolated from Lonicera japonica. Its chemical structure was determined on the basis of spectroscopic analysis, including mass spectroscopy and nuclear magnetic resonance analysis. Sweroside inhibited potent melanogenesis in m
PMID 26051519

Japanese Journal

Effect of Liquid Flow on Pigment Formation of Red Beet Hairy Roots

Journal of chemical engineering of Japan 32(3), 370-373, 1999-06
NAID 10006961496

Stereochemical Studies on the Formation of Melanin by Monophenol Monooxygenase

Chemical & pharmaceutical bulletin 37(12), 3386-3389, 1989-12-25
NAID 110003627474

Stereochemical studies on the formation of melanin by monophenol monooxygenase.

Chemical and Pharmaceutical Bulletin 37(12), 3386-3389, 1989
NAID 130003771483

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リンク元	「チロシナーゼ」「phenoloxidase」「モノフェノールモノオキシゲナーゼ」
関連記事	「monooxygenases」「monooxygenase」

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PMC	articles
PubMed	articles
NCBI	proteins

monophenol monooxygenase
	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
Search
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NCBI	proteins

TYR
Identifiers
Aliases	TYR, ATN, CMM8, OCA1, OCA1A, OCAIA, SHEP3, tyrosinase
External IDs	OMIM: 606933 MGI: 98880 HomoloGene: 30969 GeneCards: 7299
Genetically Related Diseases
Disease Name	References
	[1]
	[2]
	[3]
Gene ontology
Molecular function	• metal ion binding; • copper ion binding; • monooxygenase activity; • protein homodimerization activity; • monophenol monooxygenase activity; • oxidoreductase activity; • protein heterodimerization activity; • protein binding;
Cellular component	• cytoplasm; • integral component of membrane; • cytosol; • nucleus; • membrane; • perinuclear region of cytoplasm; • lysosome; • melanosome membrane; • Golgi-associated vesicle; • melanosome;
Biological process	• response to UV; • response to cAMP; • metabolic process; • melanin biosynthetic process from tyrosine; • response to vitamin D; • pigmentation; • thymus development; • small molecule metabolic process; • oxidation-reduction process; • eye pigment biosynthetic process; • cell proliferation; • cellular nitrogen compound metabolic process; • visual perception; • melanin biosynthetic process;
	Sources:Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	7299
	22173
	ENSG00000077498
	ENSMUSG00000004651
	P14679
	P11344
	NM_000372
	NM_011661; NM_001317397
	NP_000363.1
	NP_035791.1
	Wikidata
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