Regulation of Melanogenesis

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. 

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Mengeaud V, Ortonne JP (1994) Regulation of Melanogenesis Induced by 5-Methoxypsoralen Without Ultraviolet Light in Murine Melanoma Cells. Pigment Cell Res 7 245... 

Snyder, J. R., Hall, A., Ni-Komatsu, L., Khersonsky, S. M., Chang, Y. T., Orlow, S. J. (2005). Dissection of melanogenesis with small molecules identifies prohibitin as a regulator. Chem. Biol, 12, 477-484. 

Hu, D.N. (2000) Regulation of growth and melanogenesis of uveal melanocytes, Pigment... 

Aroca P, Garcia-Borron JC, Solano F, Lozano JA (1990) Regulation of Distal Mammalian Melanogenesis. 1 Partial Purification and Characterization of a Dopa-chrome Converting Factor Dopachrome Tautomerase. Biochim Biophys Acta 1035 266... 

Figure 4.1 Early phases of the melanogenesis pathway. The first steps are critically regulated by the melanocyte-specific enzyme tyrosinase. l-DOPA is directly formed from L-tyrosine (1) and/or indirectly via L-DOPAquinone (2). Adapted from Melanoma Research, 9, Letellier S, Gamier JP, Spy J, Stoitchkov K, Le Bricon T, Baccard M, Revol M, Kernels Y, Bousquet B. Development of metastases in mahgnant melanoma is associated with an increase of plasma L-DOPA/L-tyrosine ratio, pages 389-394, 1999, with permission from Lippincott Williams Wilkins...

Malignant melanocytes present defective melanosomes and tend to exhibit up-regulated melanogenesis. Melanogenuria (in the form of dark urine) is observed in some patients with widespread disease. End-product pigments, enzymes and melanin precursors or intermediates of the melanogenesis have therefore been measured in urine and blood from melanoma patients for more than 30 years. 

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). 

It appears from the previous discussion that melanogenesis in vivo or in vitro is regulated by various factors. Hence, to study the dynamics of melanin formation (monooxygenase reaction, i.e. constructive metabolism) and breakdown (dioxygenase reaction, i.e. catabolism of melanin precursors), a non-enzymatic melanin synthesis from tyrosine and tryptophan, respectively, was devised by Roy et al. (227), using a prototype of a monooxygenase reaction, i.e. the Udenfriend reaction (Fe+ /EDTA/ ascorbic acid) (272). 

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). 

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