BH4 (6R-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, including four aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and three NOS (NO synthase) isoenzymes. Consequently, BH4 is present in probably every cell or tissue of higher organisms and plays a key role in a number of biological processes and pathological states associated with monoamine neurotransmitter formation, cardiovascular and endothelial dysfunction, the immune response and pain sensitivity. BH4 is formed de novo from GTP via a sequence of three enzymatic steps carried out by GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. An alternative or salvage pathway involves dihydrofolate reductase and may play an essential role in peripheral tissues. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase, except for NOSs, in which the BH4 cofactor undergoes a one-electron redox cycle without the need for additional regeneration enzymes. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I. BH4 biosynthesis is controlled in mammals by hormones and cytokines. BH4 deficiency due to autosomal recessive mutations in all enzymes, except for sepiapterin reductase, has been described as a cause of hyperphenylalaninaemia. A major contributor to vascular dysfunction associated with hypertension, ischaemic reperfusion injury, diabetes and others, appears to be an effect of oxidized BH4, which leads to an increased formation of oxygen-derived radicals instead of NO by decoupled NOS. Furthermore, several neurological diseases have been suggested to be a consequence of restricted cofactor availability, and oral cofactor replacement therapy to stabilize mutant phenylalanine hydroxylase in the BH4-responsive type of hyperphenylalaninaemia has an advantageous effect on pathological phenylalanine levels in patients.
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Review Article|
August 26 2011
Tetrahydrobiopterin: biochemistry and pathophysiology
Ernst R. Werner;
Ernst R. Werner
*Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck A-6020, Austria
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Nenad Blau;
Nenad Blau
†Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Zurich CH-8032, Switzerland
‡Zürich Center for Integrative Human Physiology (ZIHP), Zürich CH-8057, Switzerland
§Research Center for Children (RCC), Zürich CH-8032, Switzerland
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Beat Thöny
Beat Thöny
1
†Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Zurich CH-8032, Switzerland
‡Zürich Center for Integrative Human Physiology (ZIHP), Zürich CH-8057, Switzerland
§Research Center for Children (RCC), Zürich CH-8032, Switzerland
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
February 14 2011
Revision Received:
May 03 2011
Accepted:
May 09 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (3): 397–414.
Article history
Received:
February 14 2011
Revision Received:
May 03 2011
Accepted:
May 09 2011
Citation
Ernst R. Werner, Nenad Blau, Beat Thöny; Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 15 September 2011; 438 (3): 397–414. doi: https://doi.org/10.1042/BJ20110293
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