Melanosomal tyrosinase

Enzymes present in melanosomes synthesize two types of melanin, eumelanin and pheomelanin. Figure 2 illustrates the proposed biosynthetic pathways of eumelanin and pheomelanin. The synthesis of eumelanin requires tyrosinase, an enzyme located in melanosomes. Tyrosinase catalyzes the conversion of tyrosine to dopa, which is further oxidized to dopaquinone. Through a series of enzymatic and nonenzymatic reactions, dopaquinone is converted to 5,6-indole quinone and then to eumelanin, a polymer. This polymer is always found attached to proteins in mammalian tissues, although the specific linkage site between proteins and polymers is unknown. Polymers affixed to protein constitute eumelanin, but the exact molecular structure of this complex has not been elucidated. Pheomelanin is also synthesized in melanosomes. The initial steps in pheomelanin synthesis parallel eumelanin synthesis, since tyrosinase and tyrosine are required to produce dopaquinone. Dopaquinone then combines with cysteine to form cysteinyldopa, which is oxidized and polymerized to pheomelanin. The exact molecular structure of pheomelanin also has not been determined. 

In normal melaninogenesis, the amino acid tyrosine is hydroxylated to form 3,4-dihydroxyphenylalanine ( dopa ), which is then oxidized to dopa-quinone. The latter moiety is polymerized to form melanin, thereafter combining with melanoprotein to form a stable complex within premelanosomes and melanosomes. Tyrosinase plays a central role in this process, by catalyzing the first step in the stated sequence. As such, it is a specific marker for melanocytic differentiation. This premise has been affirmed by studies showing that tyrosinase gene transcripts are strictly confined to melanin-producing cells. 

It has also been observed that tryptophan, like dopa, inhibits tyrosine hydroxylase and dopa oxidase activity of melanosomal tyrosinase and that its inhibitory mechanism differs from inhibition caused by non-substrate type compounds like cysteine and ascorbic acid (36). In fact, tyrosinase is inhibited by its own substrate in vitro and this inhibition mechanism differs from that caused by cysteine and ascorbic acid (242, 268). 

Chakraborty AK, Chakraborty DP (1993) The Effect of Tryptophan on Dopa-Oxidation on Melanosomal Tyrosinase. Int J Biochem 25 1277... 

Hydroquinone interferes with the production of the pigment melanin by epidermal melanocytes through at least two mechanisms it competitively inhibits tyrosinase, one of the principal enzymes responsible for converting tyrosine to melanin, and it selectively damages melanocytes and melanosomes (the organelles within which melanin is stored). 

Theos AC, Tenza D, Martina JA, Hurbain I, Peden AA, et al. 2005. Functions of adaptor protein (AP)-3 and AP-1 in tyrosinase sorting from endosomes to melanosomes. Mol Biol Cell 16 5356-5372. 

Hydroquinone is closely related to phenol and can reduce melanin production, ft appears that it can also degrade melanosomes. It has a tyrosinase-inhibiting activity and can change the membrane structure of the intracellular organelles of melanocytes. Hydroquinone acts mostly on the first stages of melanin synthesis. Its action is therefore gradual, like any tyrosinase inhibitor. 

Normal melanocytes arise from melanoblasts and undergo a series of differentiation events before reaching a Hnal end-cell differentiation state. Normal melanocytes can be arrested in their differentiation process at any given state of maturation without loss of their prohf-eration capacity. Melanocytes adhere to the basement membrane of the epidermis, and despite a resting state maintain a lifelong prohf-eration potential. Melanocytes synthesize melanin to protect various tissues such as the skin from ultraviolet radiation (UVR)-induced damage, and reach the kerantinocytes in the upper layers of the epidermis via dendrites. Tyrosinase is an essential enzyme used within the melanosomes to synthesize melanin. 

Dihydroxyphenylalanine (dopa) darkens rapidly when exposed to oxygen. The process is hastened greatly by tyrosinase (Chapter 16), which also catalyzes reaction/of Fig. 25-5, the oxidation of tyrosine to dopa. Tyrosinase is found in animals only in the organelles known as melanosomes, which are present in the melanin-producing melanocytes (Boxes 8-F ... 

Biochemical analyses of the regulation of pigmentation and proliferation have largely been confined to the population of melanoma cells grown in culture. These studies have revealed that in addition to these tyrosinase-calalyzed steps 200) various non-melanosomal regulatory factors are involved in the pathway for melanin biosynthesis 244). A short discussion of these factors is given in the following. 

Further, recent studies 132) have revealed the presence in melanocytes of a melanosomal protein different from tyrosinase, which has the ability to catalyze the rearrangement of dopachrome to DHICA. This enzymic reaction is highly stereospecific for normal L-dopachrome, is unaffected by metal chelators and has an optimal pH of about 6.8. Different names have been proposed for this enzyme, i.e. dopachrome conversion factor 132, 256), dopachrome oxidoreductase 143), dopachrome isomerase 201), and dopachrome tautomerase 4). It is of interest that another enzyme named dopaquinoneimine conversion factor seems to exist which has the remarkable ability to catalyze the decaibox-ylative rearrangement of dopachrome to DHI rather than DHICA 193). 

Seiji M, Fitzpatrick TB (1961) The Reciprocal Relationship Between Melaniza-tion and Tyrosinase Activity in Melanosomes (Melanin Granules). J Biochem 49 700... 

Seiji M, Sasaki M, Tomita Y (1978) Nature of Tyrosinase Inactivation in Melanosomes. Tohoku J Exp Med 125 233... 

Toda K, Hory Y, Eitzpatrick TB (1969) The Site of Tyrosinase Activity Within the Melanosome (Abstr). J Invest Dermatol 52 380... 

Tyrosinase (aggregated into melanosomes) (Quevedo and Smith,... 

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