A SPECIFIC TETRAHYDROBIOPTERIN BINDING DOMAIN ON TYROSINASE CONTROLS MELANOGENESIS

(6R)5,6,7,8-tetrahydrobiopterin (6-BH4) directly regulates tyrosinase activity by specifically binding to a putative 13 amino acid domain. T his domain has sequence homology to 6-BH4 binding sites already identi fied on phenylalanine hydroxylase and 4a-carbinolamine dehydratase. Fu rthermore, this binding sequence appears to have been conserved during the evolution of tyrosinase as it has also been identified in the fro g, mouse and human enzymes. 6-BH4 controls tyrosinase activity by an u ncompetitive mechanism requiring the presence of L-tyrosine for effect ive down-regulation. When L-dopa is substrate, 6-BH4 does not inhibit the enzyme implicating separate binding sites for L-dopa and L-tyrosin e on tyrosinase. Dihydropterin and 6-biopterin, the oxidation products of 6-BH4, do not inhibit tyrosinase significantly, indicating that me lanin biosynthesis is controlled by a 6-BH4/6-biopterin redox-switch m echanism which can be initiated by photo-oxidation of 6-BH4. (C) 1995 Academic Press, Inc.