PTERIDINES - METABOLIC FUNCTIONS AND CLINICAL DISORDERS

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 interes