5, 6-Dihydroxyindole from tyrosine

Figure 4-26. Raper s scheme for formation of 5,6-dihydroxyindole from tyrosine.

Eumelanins — These melanins are considered polymers derived from tyrosine derivatives, mainly 5,6-dihydroxyindole-2-carboxylic acid (DHCIA) and dihidrox-yindole (DHl), with high degrees of cross-linking. In vivo eumelanins are associated with proteins and with metals, most frequently copper, zinc, or iron. 

Figure 1. The biosynthetic pathway from tyrosine to melanin (according to Hearing and Tsukamoto, 1991 Tsukamoto et al., 1992). Tyrosinase catalyzes three different reactions in this pathway (1, 2, 3). The reaction catalyzed by the product of TRP-2, DOPAchrome tautomerase, is indicated by 4. DOPA = 3,4-dihydroxyphenylalanine DHICA = 5,6-dihydroxyin-dole-2-carboxylic acid DHI = 5,6-dihydroxyindole.

Oxidative polymerization of phenol derivatives is also important pathway in vivo, and one example is the formation of melanin from tyrosine catalyzed by the Cu enzyme, tyrosinase. The pathway from tyrosine to melanin is described by Raper (7) and Mason (8) as Scheme 8 the oxygenation of tyrosine to 4-(3,4-dihydro-xyphenyl)-L-alanin (dopa), its subsequent oxidation to dopaqui-none, its oxidative cyclization to dopachrome and succeeding decarboxylation to 5,6-dihydroxyindole, and the oxidative coupling of the products leads to the melanin polymer. The oxidation of dopa to melanin was attempted here by using Cu as the catalyst. 

Catechol melanin, a black pigment of plants, is a polymeric product formed by the oxidative polymerization of catechol. The formation route of catechol melanin (Eq. 5) is described as follows [33-37] At first, 3-(3, 4 -dihydroxyphe-nyl)-L-alanine (DOPA) is derived from tyrosine. It is oxidized to dopaquinone and forms dopachrome. 5,6-Dihydroxyindole is formed, accompanied by the elimination of C02. The oxidative coupling polymerization produces a melanin polymer whose primary structure contains 4,7-conjugated indole units, which exist as a three-dimensional irregular polymer similar to lignin. Multistep oxidation reactions and coupling reactions in the formation of catechol melanin are catalyzed by a copper enzyme such as tyrosinase. Tyrosinase is an oxidase con-... 

Melanin is an insoluble, high-molecular-weight polymer of 5,6-dihydroxyindole, which is synthesized from tyrosine (Figure 17-23). It is produced by pigment cells (melanocytes) in cytoplasmic organelles (melanosomes). In the epidermis, melanocytes are associated with keratinocytes, which contain melanosomes supplied by melanocytes via dendritic processes. Color variation in human skin reflects the amount of melanin synthesized in melanosomes. Melanin synthesis is apparently under hormonal and neural regulation. 

According to Pawelek et al. 200), the biosynthesis of melanin in Cloudman melanoma cells is a complex process and is regulated by three factors (a) a dopamine conversion factor which converts dopamine to 5,6-dihydroxyindole (13), (b) a 5,6-dihydroxyindole conversion factor which catalyzes the conversion of 5,6-dihydroxyindole to melanin and is active when cells are exposed to melanotropin (MSH), and (c) a 5,6-dihydroxyindole blocking factor which restricts melanogenesis at the 5,6-dihydroxyindole stage. They have also shown that at least three steps in the Raper-Mason scheme of melanin formation from tyrosine are catalysed by tyrosinase (Fig. 6). 

Both tryptophan and tyrosine fiamished melanin. Similar results were also obtained by Allegri et al. (3), who studied melanin synthesis from tryptophan and tyrosine spectrophotometrically. From tyrosine, p-hydro-xyphenylpyruvic acid (15), 4,4-dihydroxybiphenyl (16), 5,6-dihydroxy-indole (17), and 3,5,6-trihydroxyindole (18) were obtained in addition to melanin and from tryptophan, 5,6-dihydroxyindole (17), indole (19), anthranilic acid (20), 3-hydroxyanthranilic acid (21), indolylpyruvic acid (22), 3-hydroxypyrrol-4,5-dicarboxylic acid (23), and isatin (24). 

Melanin, the black and brown hair and skin pigment in humans and animals, also contains indole units, in particular 5,6-dihydroxyindole. It is derived from the amino acid tyrosine via DOPA (3,4-dihydroxy-phenylalanine) ... 

For many years the biosynthesis of melanin was thought to result from the spontaneous oxidation and polymerization of dopachrome produced by the tyrosinase-catalyzed hydroxylation of tyrosine to dopa and subsequent oxidation (5 ). In addition to tyrosinase, however, several enzymatic factors have been recently identified in mammalian tissues that appear to regulate melanogenesis at intermediate steps distal to those involving tyrosine and dopa. The factors include dopachrome conversion factor, dihydroxyindole blocking factor, dihydroxyindole conversion factor and dopachrome oxidoreductase (54-59). 

Natural melanins usually occur in the form of melanoproteins and thioether linkages, such as those mentioned above, may be important in the overall molecular structure. However, in this regard several attempts to demonstrate the formation of addition products between the oxidation products of either 5,6-dihydroxyindole or DOPA with certain proteins and peptides including ovalbumin [218, 224] or bovine serum albumin [224] have been unsuccessful. More recently, however, it has been shown that when tyrosine was oxidised in the presence of bovine lens protein, brown or black melanoproteins were formed [225]. On hydrolysis these pigments gave rise to a compound with similar properties to those of a (110)-type compound, which could have been formed from the oxidation of DOPA in the presence of cysteine. The thiol groups of the protein may react with some of the intermediates produced by the oxidation of tyrosine [225]. Reactions such as this may be involved in the formation of cataracts in the eye [225]. 

Melanomas are among the deadliest forms of cancer as they have a high recurrence but as yet no effective chemotherapy.(7, 2) The drug resistance of melanoma has been attributed to the presence of melanin, a redox-active polymeric pigment formed from the oxidation of tyrosine within cells.(5) The formation of melanin itself depends on fine control of oxidative chemistry a peroxide-dependent enzyme, tyrosinase, catalyzes two successive reactions, the hydroxylation of tyrosine and die oxidation of the product L-dopa, Scheme 1.(4) The product of dopa oxidation cyclizes to a 5,6-dihydroxyindole (DHI) intermediate, which is highly reactive and gives rise to black eumelanin polymers by a pathway dependent on further oxidation by oxygen.(5)... 

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