H(2)O(2) increases de novo synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin via GTP cyclohydrolase I and its feedback regulatory protein in vitiligo.
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 (6R)-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 micromol/L H(2)O(2) was the optimum concentration for the activation of the enzyme and >300 micromol/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.
Chavan
B
B
Clinical and Experimental Dermatology/Department of Biomedical Sciences, University of Bradford, Bradford, UK.
Beazley
W
W
Wood
J M
JM
Rokos
H
H
Ichinose
H
H
Schallreuter
K U
KU
D001706:Biopsy; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D016022:Case-Control Studies; D002374:Catalase / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological / Q000187:drug effects; D006136:GTP Cyclohydrolase / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction / Q000187:drug effects; D014820:Vitiligo / Q000378:metabolism* / Q000473:pathology
C101092:GCHFR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D001708:Biopterins; D006861:Hydrogen Peroxide; C038109:pseudocatalase; D002374:Catalase; D006136:GTP Cyclohydrolase; C003402:sapropterin