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PMID: 10727395 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Tetrahydrobiopterin biosynthesis, regeneration and functions.

The Biochemical journal ·Vol. 347 Pt 1 ·2000-04-01 ·Pages 1-16

Thöny B, Auerbach G, Blau N

Abstract

Tetrahydrobiopterin (BH(4)) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH(4) is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein. The enzymes that depend on BH(4) are the phenylalanine, tyrosine and tryptophan hydroxylases, the latter two being the rate-limiting enzymes for catecholamine and 5-hydroxytryptamine (serotonin) biosynthesis, all NO synthase isoforms and the glyceryl-ether mono-oxygenase. On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability.

MeSH Terms
Alcohol Oxidoreductases/chemistry,metabolism Amino Acid Sequence Animals Antioxidants/metabolism Biopterin/analogs & derivatives,biosynthesis,physiology GTP Cyclohydrolase/chemistry,metabolism Humans Mice Models, Molecular Molecular Sequence Data Molecular Structure Phosphorus-Oxygen Lyases/chemistry,metabolism Protein Conformation Rats Sequence Alignment
Chemicals
Antioxidants Biopterin Alcohol Oxidoreductases sepiapterin reductase GTP Cyclohydrolase Phosphorus-Oxygen Lyases 6-pyruvoyltetrahydropterin synthase sapropterin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Thöny B
Division of Clinical Chemistry, University Children's Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
Auerbach G
Blau N
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
Published
2000-04-01
Pages
1-16
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1220924
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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