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. This domain has sequence homology to 6-BH4 binding sites already identified on phenylalanine hydroxylase and 4a-carbinolamine dehydratase. Furthermore, this binding sequence appears to have been conserved during the evolution of tyrosinase as it has also been identified in the frog, mouse and human enzymes. 6-BH4 controls tyrosinase activity by an uncompetitive mechanism requiring the presence of L-tyrosine for effective down-regulation. When L-dopa is substrate, 6-BH4 does not inhibit the enzyme implicating separate binding sites for L-dopa and L-tyrosine on tyrosinase. Dihydropterin and 6-biopterin, the oxidation products of 6-BH4, do not inhibit tyrosinase significantly, indicating that melanin biosynthesis is controlled by a 6-BH4/6-biopterin redox-switch mechanism which can be initiated by photo-oxidation of 6-BH4.
Wood
J M
JM
Department of Biomedical Sciences, University of Bradford, W. Yorks, U.K.
Schallreuter-Wood
K U
KU
Lindsey
N J
NJ
Callaghan
S
S
Gardner
M L
ML
D000595:Amino Acid Sequence; D000818:Animals; D001487:Basidiomycota / Q000201:enzymology; D001665:Binding Sites; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000737:chemistry; D007700:Kinetics; D007980:Levodopa / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis; D051379:Mice; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000737:chemistry* / Q000378:metabolism*; D010651:Phenylalanine Hydroxylase / Q000737:chemistry; D011898:Ranidae; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism
D008543:Melanins; D001708:Biopterins; D014443:Tyrosine; D007980:Levodopa; D010651:Phenylalanine Hydroxylase; D014442:Monophenol Monooxygenase; D006836:Hydro-Lyases; C076392:pterin-4a-carbinolamine dehydratase; C003402:sapropterin