Acta
Medica Medianae
Vol. 43
Number 2, April, 2004
UDK 61
YU ISSN 0365-4478
Contact:
Gordana Bjelaković,
Institute of Biochemistry, Medical Faculty,
81 Dr Zoran Djindjic Street,
18000 Nis, Serbia and Montenegro
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PTERIDINES - METABOLIC FUNCTIONS AND CLINICAL DISORDERS
Gordana Bjelakovic,
Sasa Zivic,
Tatjana Jevtovic,
Ivana Stojanovic,
Bojko
Bjelakovic,
Jelenka Nikolic,
Dusica Pavlovic and
Gordana Kocic
Institute of Biochemistry,
Medical Faculty, Nis
Clinic of Pediatrics, Clinical center, Nis
Pteridines are widely distributed compounds in nature, associated with numerous
important physiological functions. BH4 is classified as unconjugated pteridine
distinct from folic acid and its metabolites folates representing the group of
conjugated pteridines. Unlike folic acid, which is a vitamin, BH4 can be
synthesized in organism.
Tetrahydrobiopterin (BH4) is a cofactor, important for different biological
processes, present in probably all cells and tissues of higher organisms. The
presence of persistent hyperphenylalaninemia with atypic neurological symptoms
in children, resistent to diet poor in phenylalanin, which disappears upon BH4
application, gave a strong impuls to the study of this unconjugated pteridine
metabolic functions.
BH4 is a natural cofactor of cyclic amino acid hydroxylases - phenylalanin
hydroxylase (EC 1.14.16.2), tyrosine-3-hydroxylase (EC 1.14.16.3) and
tryptophane-5-hydroxylase (EC 1.14.16.4) as well as all three isoenzymes of
nitric oxide synthase (NOS). It is neccessary for the activity of
glyceryl-ether-monooxygenase (1.14.16.5). The regeneration of
tetrahydrobiopterin is neccessary for the catalytic activity of these enzymes.
BH4 insufficiency disturbs the function of mentioned hydroxylases leading to
disorders of their products synthesis, especially 5-hydroxytryptophane, the
precursor of serotonine and L-DOPA (the precursor of catecholamines). These
metabolites function as neurotransmitters in brain and their deficit causes CNS
diseases (including disturbed psychomotoric development, disfunction of basal
ganglia and instability of body temperature. The whole content of BH4 present in
organism originates from de novo synthesis of this compound.
Tetrahydrobiopterin deficit disturbs the function of all three isoenzymes of
NOS: NOS-I or neuronal, macrophagal or inducible (NOS-II) and endothelial
(NOS-III), leading to decreased production of NO and increased production of
superoxide anion. The inhibition of GTP cyclohydrolase 1 (GCH 1), the key enzyme
in tetrahydrobiopterin biosynthesis, which uses exclusively magnesium-free GTP
as substrate, lessens vasodilation and causes increase of blood pressure.
Tetrahydrobiopterin is neccessary in the prevention of blood vessel damage and
for normal function of endothelial cells in diabetes. BH4 regulates normal
proliferation of endothelial cells (EC), which produce NO under the influence of
NOS-III. The result of decreased NO production by endothelial cells in diabetes
is disturbed angiogenesis, which directly depends on BH4 level, as a cofactor of
nitric oxide synthesis.
It is a very interesting fact that this cofactor is synthesized from GTP,
nucleoside triphosphate also neccessary for the synthesis of proteins, as well
as for the functioning of adenyl cyclase system, needed for the production of
cAMP, secondary messenger neccessary for adrenalin, glucagon and other hormones
action.
The stimulation of tetrahydrobiopterin synthesis by cytokines undoubtly points
out biological functions of pteridines in organism immune response.
Tissue distribution of BH4 indicates the fact that renal tissue is the richest
in this metabolite compared to brain and liver tissue; it calls for the need of
investigating BH4 physiological functions in kidney.
The importance of BH4 in tyrosine production (neccessary for the synthesis of
thyreoid gland hormones, T3 and T4, the production of neurotransmitters - DOPA,
dopamine, noradrenalin), synthesis of serotonine and melatonine, the function of
endothelial cells by production of NO, normal angiogenesis, maintaining of
normal blood pressure, points out further directions of the investigation of
biological functions of this very important cofactor of intermediary metabolism.
Acta Medicae Medianae 2004; 43 (2): 59-64
Key words: pteridines, tetrahydrobiopterin, BH4, metabolism, clinical disorders
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