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Regulation of tyrosinase by tetrahydropteridines and H2O2.

By John M. Wood, Bhavan Chavan, Idris Hafeez and Karin U. Schallreuter


NoRecently two alternative mechanisms have been put forward for the inhibition of tyrosinase by 6R-l-erythro 5,6,7,8-tetrahydrobiopterin (6BH4). Initially allosteric uncompetitive inhibition was demonstrated due to 1:1 binding of 10¿6 M 6BH4 to a specific domain 28 amino acids away from the CuA active site of the enzyme. Alternatively it was then shown that 10¿3 M 6BH4 inhibit the reaction by the reduction of the product dopaquinone back to l-dopa. In the study presented herein we have used two structural analogues of 6BH4 (i.e., 6,7-(R,S)-dimethyl tetrahydrobiopterin and 6-(R,S)-tetrahydromonapterin) confirming classical uncompetitive inhibition due to specific binding of the pyrimidine ring of the pterin moiety to the regulatory domain on tyrosinase. Under these conditions there was no reduction of l-dopaquinone back to l-dopa by both cofactor analogues. Inhibition of tyrosinase by 6BH4 occurs in the concentration range of 10¿6 M after preactivation with l-tyrosine and this mechanism uncouples the enzyme reaction producing H2O2 from O2. Moreover, a direct oxidation of 6BH4 to 7,8-dihydrobiopterin by tyrosinase in the absence of the substrate l-tyrosine was demonstrated. The enzyme was activated by low concentrations of H2O2 (<0.3 × 10¿3 M), but deactivated at concentrations in the range 0.5¿5.0 × 10¿3 M. In summary, our results confirm a major role for 6BH4 in the regulation of human pigmentation

Topics: Tyrosinase, Tyrosine, H2O2, Tetrahydrobiopterin, Melanogenesis
Year: 2004
DOI identifier: 10.1016/j.bbrc.2004.10.185
OAI identifier:
Provided by: Bradford Scholars
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