PMID: 01727395: (BH(4)) cofactor and PD, CD, AD, etc

[janet paterson <janet313@xxxxxxxxxxx>]

Tetrahydrobiopterin biosynthesis, regeneration and functions.

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.


Biochem J 2000 Apr 1;347(Pt 1):1-16
Thony B, Auerbach G, Blau N
University Children's Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland.

PMID: 10727395

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janet paterson
53 now / 41 dx / 37 onset
a new voice: 
613 256 8340 PO Box 171 Almonte Ontario Canada K0A 1A0