Document Detail

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.
MedLine Citation:
PMID:  19101819     Owner:  NLM     Status:  MEDLINE    
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.
B Chavan; W Beazley; J M Wood; H Rokos; H Ichinose; K U Schallreuter
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-12-22
Journal Detail:
Title:  Journal of inherited metabolic disease     Volume:  32     ISSN:  1573-2665     ISO Abbreviation:  J. Inherit. Metab. Dis.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-02-04     Completed Date:  2009-05-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7910918     Medline TA:  J Inherit Metab Dis     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  86-94     Citation Subset:  IM    
Clinical and Experimental Dermatology/Department of Biomedical Sciences, University of Bradford, Bradford, UK.
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MeSH Terms
Biopterin / analogs & derivatives*,  biosynthesis
Case-Control Studies
Catalase / physiology
Dose-Response Relationship, Drug
Down-Regulation / physiology
Enzyme Activation / drug effects
Epidermis / metabolism,  pathology
Feedback, Physiological / drug effects
GTP Cyclohydrolase / metabolism,  physiology*
Hydrogen Peroxide / metabolism,  pharmacology*
Intracellular Signaling Peptides and Proteins / metabolism,  physiology*
Oxidation-Reduction / drug effects
Vitiligo / metabolism*,  pathology
Reg. No./Substance:
0/GCHFR protein, human; 0/Intracellular Signaling Peptides and Proteins; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 7722-84-1/Hydrogen Peroxide; EC 1.11.1.-/pseudocatalase; EC; EC Cyclohydrolase

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