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H 2 O 2 increases de novo synthesis of (6 R )‐ L ‐erythro‐5,6,7,8‐tetrahydrobiopterin via GTP cyclohydrolase I and its feedback regulatory protein in vitiligo
Author(s) -
Chavan B.,
Beazley W.,
Wood J. M.,
Rokos H.,
Ichinose H.,
Schallreuter K. U.
Publication year - 2009
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-008-0971-1
Subject(s) - tetrahydrobiopterin , gtp cyclohydrolase i , phenylalanine , enzyme , biopterin , gtp' , protein biosynthesis , chemistry , amino acid , stereochemistry , biochemistry , cofactor
Summary Patients with vitiligo accumulate up to 10 −3 mol/L concentrations of H 2 O 2 in their epidermis, which in turn affects many metabolic pathways in this compartment, including the synthesis and recycling of the cofactor (6 R )‐ l ‐erythro‐5,6,7,8‐tetrahydrobiopterin (6BH 4 ). De novo synthesis of 6BH 4 is dependent on the rate‐limiting enzyme GTP cyclohydrolase I (GTPCHI) together with its feedback regulatory protein (GFRP). This step is controlled by 6BH 4 and the essential amino acid l ‐phenylalanine. In the study presented here we wanted to investigate whether H 2 O 2 affects the GTPCHI/GFRP cascade in these patients. Our results demonstrated concentration‐dependent regulation of rhGTPCHI where 100 μmol/L H 2 O 2 was the optimum concentration for the activation of the enzyme and >300 μmol/L resulted in a decrease in activity. Oxidation of GFRP and GTPCHI does not affect feedback regulation via l ‐phenylalanine and 6BH 4 . In vitiligo a constant upregulation of 6BH 4 de novo synthesis results from epidermal build up of l ‐phenylalanine that is not controlled by H 2 O 2 . Taking the results together, 6BH 4 de novo synthesis is controlled by H 2 O 2 in a concentration‐dependent manner, but H 2 O 2 ‐mediated oxidation does not affect the functionality of the GTPCHI/GFRP complex.