The IFPCS presidential lecture: a chemist's view of melanogenesis.
The significance of our understanding of the chemistry of melanin and melanogenesis is reviewed. Melanogenesis begins with the production of dopaquinone, a highly reactive o-quinone. Pulse radiolysis is a powerful tool to study the fates of such highly reactive melanin precursors. Based on pulse radiolysis data reported by Land et al. (J Photochem Photobiol B: Biol 2001;64:123) and our biochemical studies, a pathway for mixed melanogenesis is proposed. Melanogenesis proceeds in three distinctive steps. The initial step is the production of cysteinyldopas by the rapid addition of cysteine to dopaquinone, which continues as long as cysteine is present (1 microM). The second step is the oxidation of cysteinyldopas to give pheomelanin, which continues as long as cysteinyldopas are present (10 microM). The last step is the production of eumelanin, which begins only after most cysteinyldopas are depleted. It thus appears that eumelanin is deposited on the preformed pheomelanin and that the ratio of eu- to pheomelanin is determined by the tyrosinase activity and cysteine concentration. In eumelanogenesis, dopachrome is a rather stable molecule and spontaneously decomposes to give mostly 5,6-dihydroxyindole. Dopachrome tautomerase (Dct) catalyses the tautomerization of dopachrome to give mostly 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Our study confirmed that the role of Dct is to increase the ratio of DHICA in eumelanin and to increase the production of eumelanin. In addition, the cytotoxicity of o-quinone melanin precursors was found to correlate with binding to proteins through the cysteine residues. Finally, it is still unknown how the availability of cysteine is controlled within the melanosome.
Ito
Shosuke
S
Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan. sito@fujita-hu.ac.jp
D000818:Animals; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D008543:Melanins / Q000737:chemistry*; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D008956:Models, Chemical; D013997:Time Factors
D008543:Melanins; C018362:pheomelanin; C041877:eumelanin; D003545:Cysteine