title: Inhibitory effects of melanin monomers, dihydroxyindole-2-carboxylic acid (DHICA) and dihydroxyindole (DHI) on mammalian tyrosinase, with a special reference to the role of DHICA/DHI ratio in melanogenesis.
abstract: DOPAchrome tautomerase (DCT) is known to control the ratio of DHICA/DHI formed within the melanocyte, but physiologic significance of this activity is not yet fully elucidated. In this study the two melanin monomers are shown to inhibit with different efficacy the initial, tyrosinase-controlled, melanogenic reaction, namely conversion of L-tyrosine to DOPAchrome (2-carboxy-2,3-dihydroindole-5,6-quinone). This is demonstrated in the test tube assay system whereby formation of DOPAchrome is catalyzed by i) isolated premelanosomes (PMS), ii) tyrosinase-rich PMS glycoproteins, or iii) tyrosinase purified from fibroblasts transfected with human tyrosinase gene. Both DHI and DHICA suppress the conversion of L-tyrosine to DOPAchrome when added to reaction mixture but the inhibitory effect is far more strongly pronounced by DHI. DHI inhibits both activities of tyrosinase--tyrosine-hydroxylation and DOPA-oxidation--more strongly than DHICA. The different extent of inhibition is shown to reflect i) the ability of the two monomers to compete with tyrosinase substrates for the enzyme's active center and ii) the rate of interaction between melanin monomers and DOPAquinone. Consequently, we demonstrate that the tyrosinase-catalyzed DOPAchrome formation can be modulated by the ratio of DHICA/DHI among melanin monomers with the increased proportion of DHICA resulting in more efficient DOPAchrome formation. These results raise the possibility that DOPAchrome tautomerase plays a role in positive control of the tyrosinase-catalyzed early phase of melanogenesis.
authors.affiliation: Mishima Insitute for Dermatological Research, Kobe Kaisei Hospital, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Wilczek
authors.forename: Y
authors.initials: Y
authors.lastname: Mishima
mesh_terms: D000818:Animals; D006224:Cricetinae; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism; D007700:Kinetics; D008543:Melanins / Q000096:biosynthesis* / Q000494:pharmacology*; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
chemical_list: D045563:Indolequinones; D007211:Indoles; D008543:Melanins; D011809:Quinones; C001123:dopachrome; D014443:Tyrosine; C030692:5,6-dihydroxy-2-indolylcarboxylic acid; D014442:Monophenol Monooxygenase; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase