The 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidase activity of human tyrosinase

Melanin synthesis in mammals is catalysed by at least three enzymic protein s, tyrosinase (monophenol dihydroxyphenylalanine:oxygen oxidoreductase, EC 1.14.18.1) and tyrosinase-related proteins (tyrps) 1 and 2, whose genes map to the albino, brown and slaty loci in mice, respectively. Tyrosinase cata lyses the rate-limiting generation of L-dopaquinone from L-tyrosine and is also able to oxidize L-dopa to L-dopaquinone. Conversely, mouse tyrpl, but not tyrosinase, catalyses the oxidation of the indolic intermediate 5,6-dih ydroxyindole-2-carboxylic acid (DHICA) into the corresponding 5,6-indolequi none-2-carboxylic acid, thus promoting the incorporation of DHICA units int o eumelanin. The catalytic activities of the human melanogenic enzymes are still debated. TYRP1 has been reported to lack DHICA oxidase activity, wher eas tyrosinase appears to accelerate DHICA consumption, thus raising the qu estion of DHICA metabolism in human melanocytes. Here we have used two diff erent approaches, comparison of the catalytic activities of human melanocyt ic cell lines expressing the full set of melanogenic enzymes or deficient i n TYRP1, and transient expression of TYR and tyr genes in COS7 cells, to de monstrate that human tyrosinase actually functions as a DHICA oxidase, as o pposed to the mouse enzyme. Therefore, human tyrosinase displays a broader substrate specificity than its mouse counterpart, and might be at least par tially responsible for the incorporation of DHICA units into human eumelani ns.