MetaCyc Pathway: eumelanin biosynthesis
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: eumelanin biosynthesis

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: melanochrome biosynthesis, melanogenesis

Superclasses: BiosynthesisOther Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Mus musculus

Expected Taxonomic Range: Bacteria , Eukaryota

Eumelanin is a common type of melanin pigment, which is found in hair and skin. There are two types of eumelanin, black and brown, which differ by their pattern of polymer bonds. A small amount of black eumelanin in the absence of other pigments causes grey hair, while a small amount of brown eumelanin in the absence of other pigments causes yellow (blond) color hair.

Spectroscopic studies of the biosynthesis of eumelanin showed that it takes place in three chromophoric phases. The first phase corresponds to the formation of the red pigment L-dopachrome (λmax 475 nm) (see L-dopachrome biosynthesis). The second phase corresponds to a purple intermediate, which was designated melanochrome, with a broad absorption maximum at 540 nm, and the third phase is characterized by a general absorption due to eumelanin [Napolitano85].

The oxidation of L-dopachrome to melanochrome occurs spontaneously in vitro but has been shown to be under enzymatic control in vivo. L-dopachrome is converted into two compounds - a spontaneous decarboxylation to 5,6-dihydroxyindole, and an enzymatic tautomerization to 5,6-dihydroxyindole-2-carboxylate [Korner85]. Both of these products are then oxidized to quinones, which are polymerized to form melanochrome and eventually eumelanin.

In vertebrates, the pathway involves the activities of three related proteins, all members of the tyrosinase gene family: tyrosinase ( TYR), tyrosinase-related protein 1 ( Tyrp1) and tyrosinase-related protein 2 ( Dct).

The enzymatic activities of tyrosinase and tyrosinase-related protein 2 ( L-dopachrome tautomerase) are well established. Tyrosinase is the initial, rate-limiting enzyme of melanogenesis, catalyzing the first two steps from L-tyrosine via L-dopa to dopaquinone, which goes through a series of spontaneous reactions yielding L-dopachrome (see L-dopachrome biosynthesis). Subsequently, the Dct-encoded L-dopachrome tautomerase converts L-dopachrome into 5,6-dihydroxyindole-2-carboxylate (DHICA).

The role of the third family member, Tyrp1, is less clear. Despite its structural similarity to Tyr and Dct, the enzymatic function of Tyrp1 is controversial and might be species-specific [Sarangarajan01]. A 5,6-dihydroxyindole-2-carboxylate monooxygenase (DHICA oxidase) activity has been demonstrated for the murine Tyrp1 protein [JimenezCervante94, Kobayashi94, Kobayashi94a], but in humans TYR and not TYRP1 performs this function [Boissy98, Olivares01]. As Tyr and Tyrp1 are part of the 'melanogenic complex' and are known to form heterodimers, it is possible that the main function of human Tyrp1 is to stabilize tyrosinase [Winder94, Kobayashi98, Kobayashi07].

The two products of L-dopachrome oxidation, indole-5,6-quinone and indole-5,6-quinone-2-carboxylate, polymerize to form a mixture of different dimers and trimers, known under the name melanochrome. The polymerization can be induced by the presence of certain metal ions such as Ni2+ or Zn2+ [Napolitano85], but could also be catalyzed enzymatically by tyrosinase or by peroxidases. Different routes were shown to result in the formation of different compounds. For example, studies using 5,6-dihydroxyindole as substrate found that the predominant product was the 2-2'-linked dimer 2-(5,6-dihydroxy-1H-indol-2-yl)-1H-indole-5,6-diol when metal ions were added, but the 2-4'-linked dimer 2-(5,6-dihydroxy-1H-indol-4-yl)-1H-indole-5,6-diol when tyrosinase was added [Napolitano85]. When peroxidase was added to the reaction, the 2-4'-linked dimer was still formed, but a third product, the 2-7'-linked dimer 2-(5,6-dihydroxy-1H-indol-7-yl)-1H-indole-5,6-diol was also present [Prota91]. Similarly, when indole-5,6-quinone-2-carboxylate was used as substrate, the predominant product was the 4-4'-linked dimer 4-(2-carboxylato-5,6-dihydroxy-1H-indol-4-yl)-5,6-dihydroxy-1H-indole-2-carboxylate when metal ions were added, but the 4-7'-linked dimer 7-(2-carboxylato-5,6-dihydroxy-1H-indol-4-yl)-5,6-dihydroxy-1H-indole-2-carboxylate when tyrosinase was added [Prota91].

Defects in TYR result in various forms of albinism. Mutations in TYRP1 in mice result in brown fur, but mutations in the human gene result in a form of oculocutaneous albinism (OCA3).

Created 23-Apr-2010 by Caspi R, SRI International


Boissy98: Boissy RE, Sakai C, Zhao H, Kobayashi T, Hearing VJ (1998). "Human tyrosinase related protein-1 (TRP-1) does not function as a DHICA oxidase activity in contrast to murine TRP-1." Exp Dermatol 7(4);198-204. PMID: 9758418

JimenezCervante94: Jimenez-Cervantes C, Solano F, Kobayashi T, Urabe K, Hearing VJ, Lozano JA, Garcia-Borron JC (1994). "A new enzymatic function in the melanogenic pathway. The 5,6-dihydroxyindole-2-carboxylic acid oxidase activity of tyrosinase-related protein-1 (TRP1)." J Biol Chem 269(27);17993-8000. PMID: 8027058

Kobayashi07: Kobayashi T, Hearing VJ (2007). "Direct interaction of tyrosinase with Tyrp1 to form heterodimeric complexes in vivo." J Cell Sci 120(Pt 24);4261-8. PMID: 18042623

Kobayashi94: Kobayashi T, Urabe K, Winder A, Jimenez-Cervantes C, Imokawa G, Brewington T, Solano F, Garcia-Borron JC, Hearing VJ (1994). "Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis." EMBO J 13(24);5818-25. PMID: 7813420

Kobayashi94a: Kobayashi T, Urabe K, Winder A, Tsukamoto K, Brewington T, Imokawa G, Potterf B, Hearing VJ (1994). "DHICA oxidase activity of TRP1 and interactions with other melanogenic enzymes." Pigment Cell Res 7(4);227-34. PMID: 7855068

Kobayashi98: Kobayashi T, Imokawa G, Bennett DC, Hearing VJ (1998). "Tyrosinase stabilization by Tyrp1 (the brown locus protein)." J Biol Chem 273(48);31801-5. PMID: 9822646

Korner85: Korner AM, Gettins P (1985). "Synthesis in vitro of 5,6-dihydroxyindole-2-carboxylic acid by dopachrome conversion factor from Cloudman S91 melanoma cells." J Invest Dermatol 85(3);229-31. PMID: 4031539

MunozMunoz09: Munoz-Munoz JL, Garcia-Molina F, Varon R, Tudela J, Garcia-Canovas F, Rodriguez-Lopez JN (2009). "Generation of hydrogen peroxide in the melanin biosynthesis pathway." Biochim Biophys Acta 1794(7);1017-29. PMID: 19374959

Napolitano85: Napolitano, A., Corradini, M. G., Prota, G. (1985). "A reinvestigation of the structure of melanochrome." Tetrahedron Letters 26(23):2805-2808.

Olivares01: Olivares C, Jimenez-Cervantes C, Lozano JA, Solano F, Garcia-Borron JC (2001). "The 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidase activity of human tyrosinase." Biochem J 354(Pt 1);131-9. PMID: 11171088

Prota91: Prota, G., Misuraca, G., Napolitano, A., Palumbo, A. (1991). "Regulatory mechanisms in melanin pigmentation: a biomimetic approach." in Chemistry and properties of biomolecular systems, Ed. E. Rizzarelli, Kluwer Academic Publishers.

Sarangarajan01: Sarangarajan R, Boissy RE (2001). "Tyrp1 and oculocutaneous albinism type 3." Pigment Cell Res 14(6);437-44. PMID: 11775055

Winder94: Winder A, Kobayashi T, Tsukamoto K, Urabe K, Aroca P, Kameyama K, Hearing VJ (1994). "The tyrosinase gene family--interactions of melanogenic proteins to regulate melanogenesis." Cell Mol Biol Res 40(7-8);613-26. PMID: 7787879

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Aroca90: Aroca P, Garcia-Borron JC, Solano F, Lozano JA (1990). "Regulation of mammalian melanogenesis. I: Partial purification and characterization of a dopachrome converting factor: dopachrome tautomerase." Biochim Biophys Acta 1035(3);266-75. PMID: 2169885

Barton88: Barton DE, Kwon BS, Francke U (1988). "Human tyrosinase gene, mapped to chromosome 11 (q14----q21), defines second region of homology with mouse chromosome 7." Genomics 3(1);17-24. PMID: 3146546

Bouchard89: Bouchard B, Fuller BB, Vijayasaradhi S, Houghton AN (1989). "Induction of pigmentation in mouse fibroblasts by expression of human tyrosinase cDNA." J Exp Med 169(6);2029-42. PMID: 2499655

Chakraborty92: Chakraborty AK, Orlow SJ, Pawelek JM (1992). "Evidence that dopachrome tautomerase is a ferrous iron-binding glycoprotein." FEBS Lett 302(2);126-8. PMID: 1633843

Decker00: Decker H, Dillinger R, Tuczek F (2000). "How Does Tyrosinase Work? Recent Insights from Model Chemistry and Structural Biology This work was supported by the Medicine and Science Center of the University of Mainz (H.D.) and the Deutsche Forschungsgemeinschaft (F.T., R.D.). The authors thank M.Moller for help with the graphical artwork." Angew Chem Int Ed Engl 39(9);1591-1595. PMID: 10820445

Fukai95: Fukai K, Holmes SA, Lucchese NJ, Siu VM, Weleber RG, Schnur RE, Spritz RA (1995). "Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism." Nat Genet 9(1);92-5. PMID: 7704033

Furumura98: Furumura M, Solano F, Matsunaga N, Sakai C, Spritz RA, Hearing VJ (1998). "Metal ligand-binding specificities of the tyrosinase-related proteins." Biochem Biophys Res Commun 242(3);579-85. PMID: 9464259

Giebel91: Giebel LB, Strunk KM, Spritz RA (1991). "Organization and nucleotide sequences of the human tyrosinase gene and a truncated tyrosinase-related segment." Genomics 9(3);435-45. PMID: 1903356

Halaban00: Halaban R, Svedine S, Cheng E, Smicun Y, Aron R, Hebert DN (2000). "Endoplasmic reticulum retention is a common defect associated with tyrosinase-negative albinism." Proc Natl Acad Sci U S A 97(11);5889-94. PMID: 10823941

Halaban90: Halaban R, Moellmann G (1990). "Murine and human b locus pigmentation genes encode a glycoprotein (gp75) with catalase activity." Proc Natl Acad Sci U S A 87(12);4809-13. PMID: 1693779

Jackson88a: Jackson IJ (1988). "A cDNA encoding tyrosinase-related protein maps to the brown locus in mouse." Proc Natl Acad Sci U S A 85(12);4392-6. PMID: 3132713

Jackson92: Jackson IJ, Chambers DM, Tsukamoto K, Copeland NG, Gilbert DJ, Jenkins NA, Hearing V (1992). "A second tyrosinase-related protein, TRP-2, maps to and is mutated at the mouse slaty locus." EMBO J 11(2);527-35. PMID: 1537334

Kwon87: Kwon BS, Haq AK, Pomerantz SH, Halaban R (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. PMID: 2823263

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

MercadoBlanco93: Mercado-Blanco J, Garcia F, Fernandez-Lopez M, Olivares J (1993). "Melanin production by Rhizobium meliloti GR4 is linked to nonsymbiotic plasmid pRmeGR4b: cloning, sequencing, and expression of the tyrosinase gene mepA." J Bacteriol 175(17);5403-10. PMID: 8366027

Nakamura02: Nakamura E, Miyamura Y, Matsunaga J, Kano Y, Dakeishi-Hara M, Tanita M, Kono M, Tomita Y (2002). "A novel mutation of the tyrosinase gene causing oculocutaneous albinism type 1 (OCA1)." J Dermatol Sci 28(2);102-5. PMID: 11858948

Palumbo91: Palumbo A, Solano F, Misuraca G, Aroca P, Garcia Borron JC, Lozano JA, Prota G (1991). "Comparative action of dopachrome tautomerase and metal ions on the rearrangement of dopachrome." Biochim Biophys Acta 1115(1);1-5. PMID: 1958700

Shibahara86: Shibahara S, Tomita Y, Sakakura T, Nager C, Chaudhuri B, Muller R (1986). "Cloning and expression of cDNA encoding mouse tyrosinase." Nucleic Acids Res 14(6);2413-27. PMID: 3008090

Shibahara88: Shibahara S, Tomita Y, Tagami H, Muller RM, Cohen T (1988). "Molecular basis for the heterogeneity of human tyrosinase." Tohoku J Exp Med 156(4);403-14. PMID: 2854305

Solano94: Solano F, Martinez-Liarte JH, Jimenez-Cervantes C, Garcia-Borron JC, Lozano JA (1994). "Dopachrome tautomerase is a zinc-containing enzyme." Biochem Biophys Res Commun 204(3);1243-50. PMID: 7980602

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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