Plasman biopteriini on mitatavissa

http://www.biopku.org/pdf/shintakuMGM.pdf

Cardiovascular Pharmacology

David G. Harrison, ... Li Li, in Advances in Pharmacology, 2010

Structural Properties

Biopterin and its related molecules belong to a class of compounds that include pterins, folates, riboflavin, lumazines, and alloxazines. These all contain two or three heterocyclic six-membered rings and are ubiquitous in plants and animals. 

Pterins possess one pyrazine and one pyrimadine ring (Fig. 1), and were named so because they were first identified as a pigment in butterfly wings (Gates, 1947).

 The major pterins in vertebrates are BH₄, which has hydrogens at the 5, 6, 7, and 8 positions, and its oxidized form, 7,8-dihydrobiopterin (BH₂) (Fig. 1).

BH₄ is important in mammalian biology because it serves as a critical cofactor for the aromatic amino acid hydroxylases and the NOSs (Bigham et al., 1987).

 The three amino acid hydroxylases include phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, ultimately leading to formation of tyrosine, dopamine, and serotonin. In the case of these enzymes, BH₄ is converted to the quinoid form of BH₂ (qBH₂) and must be converted back to BH₄ via a salvage pathway (discussed below).

 Genetic deficiencies of BH₄ are uncommon, but cause a form of phenylketonuria due to reduced conversion of phenylalanine to tyrosine (Tada et al., 1970).

A New Era of Catecholamines in the Laboratory and Clinic

Hiroshi Ichinose*¹, ... Kazunao Kondo^†, in Advances in Pharmacology, 2013

4.3

Developmental alteration of dopamine in partial BH4-deficient mice

We investigated the effects of low biopterin availability on the biosynthesis of the monoamine neurotransmitters in the brain during the early postnatal period (Homma et al., 2011). The levels of biopterin within the brains of the wild-type mice gradually decreased from postnatal day 0 (P0) to P28 (Fig. 3.6). The BH4 levels within the brains of the Spr^−/− or the DPS-Pts^−/− mice were significantly lower than that of the wild-type mice and were consistent at ~20–30% of the wild-type levels during the time points examined.

We next measured the levels of monoamine neurotransmitters and their metabolites in the brain. In the wild-type mice, the dopamine levels were markedly increased during postnatal days (Fig. 3.7). The elevation in dopamine levels might reflect the postnatal maturation of the dopaminergic system in the mice. Dopamine levels in the brains of the DPS-Pts^−/− or the Spr^−/− mice were ~50% less than those of the wild-type mice at P0. Unlike the wild-type mice, however, these BH4-deficient mice exhibited almost no elevation in dopamine levels during early postnatal development. As a result, the extents of dopamine deficiency compared with that of the wild-type mice were more severe at P7 and P14 than at P0.

Because we observed significantly reduced TH protein levels in the BH4-deficient mice, we examined the developmental alterations in the TH protein levels from P0 to P14 in the Spr^−/− mice and to P28 in the DPS-Pts^−/− mice and the wild-type mice. The TH protein levels in the brains of the wild-type mice were markedly elevated from P0 to P14, similar to the increase in dopamine levels. Interestingly, the increased TH protein levels in the wild-type mice were strikingly abrogated in the Spr^−/− and the DPS-Pts^−/− mice. In contrast, the AADC protein levels were unchanged between P0 and P14 for all of the genotypes examined (Homma et al., 2011).

We also performed immunohistochemical analyses in the striatum of the wild-type and the Spr^−/− mice from P0 to P21. In the wild-type mice, the striatal TH immunoreactivity gradually increased from P0 to P21. The Spr^−/− mice exhibited almost no increase in TH immunoreactivity. Furthermore, Spr^−/− mice exhibited hindlimb clasping at P14, whereas the extent of clasping was less in Spr^−/− mice than in DPS-Pts^−/− mice.

Although both the DPS-Pts^−/− and the Spr^−/− mice suffered from similar partial biopterin deficiency, we observed differences at the levels of immunohistochemical analysis and behavioral manifestation. 

 In the DPS-Pts^−/− mice, the TH immunoreactivity in the striatum was weaker in the striosomes than in the surrounding matrix, and these mice exhibited hypokinetic hindlimb dystonia, whereas the Spr^−/− mice were hypokinetic and presented tremor-like shaking. Future investigations will explore the mechanisms underlying the differences between these two mice models and whether they are caused by differences in the noradrenergic activity, as the BH4 synthesis in the noradrenergic neurons in the DPS-Pts^−/− mice is restored.