Of dopachrome

Figure 5. The pH dependence of rate constant of dopachrome and melanin formation (Q) imidazole-Cu (O) PVIm-Cu (A) PIPo—Cu (9) tyrosinase 30°C, air, phosphate buffer... 

From Lys hydrochloride pyrolyzed in vacuo at 600°C for 8-10 min, a tricyclic compound 134 is formed in low yield (80TL2679). Cystine reacts with dopachrome to give an unstable product, but the methyl ester of dopachrome gave a stable pyrrolo[2,3-/i][l,4]benzothiazine 135 (87T5357). 

In 1937 Arnow showed that tyrosine could be converted into DOPA by ultraviolet radiation51 and that the DOPA produced in this manner was subsequently destroyed by further irradiation, the solutions becoming red-brown in color (presumably due to the formation of dopachrome).51 In 1939 Konzett and Weis reported that the blood pressure-raising effect of adrenaline solutions was lost on ultraviolet irradiation and that the solutions became colored and fluorescent the initial red color fades to reddish yellow.62 This phenomenon suggests the initial formation of adrenochrome, followed by its isomerization to adrenolutin, both of these compounds being virtually void of pressor activity. Similarly to the radiation-induced hydroxylation of tyrosine mentioned above, synephrine was first... 

Many assays for tyrosinase activity have been developed. Procedures in the literature include use of the oxygen electrode, oxidation of tyrosine followed at 280 nm, and oxidation of dopa followed at 475 nm. The most convenient assay involves following the tyrosinase-catalyzed oxidation of dopa by monitoring the initial rate of formation of dopachrome at 475 nm (Figure E5.8). 

Kinetically slow steps in the formation of melanin from DOPA are the formation of dopaquinone from DOPA (step 1, kD), the reaction of dopachrome to dihydroxyindole (step 2), and the polymerization to form melanin (step 3, kM). Step 1 and step 2 proceed with about the same rate in the oxidative coupling polymerization catalyzed by tyrosinase. However, step 1 becomes remarkably slow when a macromolecule-metal complex is used as a catalyst. The copper complex in poly(l-vinylimidazole-co-vinylpyrrolidone) has been found [38] to act as an excellent catalyst and to exhibit the highest activity for melanin formation. The ratio of the rate constants ( m/ d) is approximately 3 (tyrosinase... 

Condensation of dopachrome methyl or ethyl esters with cysteine ethyl ester in pH 6.8 aqueous phosphate buffer led to the l,2-dihydro-3//,8//-pyrrolo[2,3-/ ][l,4]benzothiazines (87), as shown in... 

Purification procedure via treatment with HCl Ultrastructural and cytochemical study Magnesium dependence and hair graying Study of dopachrome oxidoreductase and tyrosinase activity Correlation between melanin charge and intensity of ESR signal of irradiated hair... 

Some reports associate the rearrangement of dopachrome to DI in melanoma with an enzyme distal from tyrosinase (179-182) characterized as an oxidoreductase (183). Owing to the preliminary nature of the supporting experiments, however, the regulatory effect may be associated with the catalytic effect of metal ions rather than that of the new enzyme (184). 

Other workers (87SC1815) reported a convenient one-pot synthesis of the acid 2 and its benzyl ester involving oxidation of dopa benzyl ester 32 with ceric ammonium nitrate followed by treatment with zinc acetate to induce isomerization of dopachrome... 

At pH 7.4 metal ions promote the non-decarboxylative pathway to the acid 2, most likely by enhancing the acidity of the H-2 proton (87BBA203). Notably, however, at pH 5.5, aluminium ions promote the rapid decarboxylative rearrangement of dopachrome leading to 5,6-dihydroxyindole 1 rather than the acid 2 (03MI1689). 

In the Raper-Mason scheme of melanin biosynthesis (Fig. 5) 216, 217), tyrosine is enzymatically converted via dopa to dopaquinone. The subsequent oxidation steps leading to melanin formation depend upon the biochemical environment of the reaction site. However, the melanization process in vitro or in vivo has two important features the rearrangement of dopachrome and the oxidative polymerization of 5,6-dihydroxyindoles leading to melanochrome. 

For the rearrangement of dopachrome, one possible mechanism which has been accepted by different authors 66, 218, 255), involves a hydrogen shift from position 3 and the formation of a quinone methide followed by subsequent decarboxylation to 13. Analysis of the anal5hical data from various laboratories 66, 108, 202) has shown that the yield of DHI vs DHICA is about 95 to 5, at a pH range from 3 to 8.5 which indicates that tyrosinase-catalyzed synthetic dopamelanin is made up mainly of DHI-derived units, as proposed by Mason 163). Hence, the... 

The presence of certain metal ions, especially Cu, Fe, Zn etc., in melanin biosynthesis, however, accelerates the non-decarboxylating rearrangement of dopachrome leading to the formation of DHICA rather than DHI (50, 190). 

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). 

The oxidation of DHICA was also studied in the absence and presence of DHI, and two dimers (191) and one mixed dimer (180) were identified. The overall results obtained in the oxidation of DHI or DHICA at the melanochrome stage support the concept of eumelanin as an intimate mixture of homopolymers of DHI and DHICA, and copolymers of the two indole units in different proportions, the latter depending upon the ratio of formation of DHI and DHICA in the rearrangement of dopachrome. 

Costantini C, Crescenzi O, Prota G (1991) Mechanism of the Rearrangement of Dopachrome to 5,6-Dihydroxyindole. Tetrahedron Lett 31 3849... 

Palumbo A, d Ischia M, Misuraca G, Prota G (1987) Effect of Metal Ions on the Rearrangement of Dopachrome. Biochim Biophys Acta 925 203... 

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). 

Dopachrome conversion factor catalyzes the decolorization of dopachrome. The mechanism of this conversion apparently involves an isomeric rearrangement of a hydrogen atom from one position of the dopachrome molecule to another, an intramolecular oxidoreduction which results in a tautomeric shift forming 5,6-dihydroxyindole-2-... 

More recently the oxidation of tyrosine methyl ester with potassium nitrosodisulphonate (Fremy s salt), was shown to give 2-carbomethoxy-5,6-dihydroxyindole, via the intermediate formation of dopachrome methyl ester [81a]. It was also shown that tyrosine containing peptides are oxidised by Fremy s salt in a similar manner to that previously described for their enzymatic oxidation [cf. 29]. 

The internal oxidation-reduction reaction first described by Raper to explain the decolorisation of dopachrome (68) solutions [14], which were formed during the melanisation of DOPA, is undoubtedly the most characteristic reaction of the aminochromes [26-29]. 

Recently, it was foimd that kojic add-tripeptide amides showed similar tyrosinase inhibitoiy activities to those of kojic add-tripeptide free adds but exhibited superior storage stability than those of kojic acid and kojic add-trip>eptide free acids (Noh, 2007). To find further kojic acid derivatives with higher tyrosinase inhibitory activity, stability, and synthetic effidency, a library of kojic add-amino acid amides (KA-AA-NH2) prepared and screened for their tyrosinase inhibitoiy activities. It was also confirmed that the kojic add-phenylalanine amides reduced the amount of dopachrome production during the melanin formation. It was suggested that a tyrosinase inhibition mechanism of KA-AA-NH2 based on the possible hydrophobic interadions between the side chain of KA-AA-NH2 and tyrosinase active site by a docking program (Noh, 2009 Kim, 2004). 

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