Tetrahydrobiopterin effects

It has been shown that the activity of NO synthases is regulated by cofactors calcium binding protein calmodulin and tetrahydrobiopterin (H4B). Abu-Soud et al. [149] have studied the effect of H4B on the activity of neuronal nNOS I, using the isolated heme-containing oxygenase domain nNOSoxy. It was found that nNOSoxy rapidly formed an oxygenated complex in the reaction with dioxygen, which dissociated to produce superoxide (Reaction (6)) ... 

Werner-Felmayer G, Golderer G, Werner ER (2002) Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects. Curr Drug Metab 3 159-173... 

Miura, H., Kitagami, T., Ozaki, N. (2007). Suppressive effect of paroxetine, a selective serotonin uptake inhibitor, on tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice. Synapse, 61, 698-706. 

Tetrahydrobiopterin is not a vitamin, because it can be synthesized from GTP, as shown in Figure 10.2 (Thony et al., 2000). It is the coenzyme for mixed-function oxidases phenylalanine, tyrosine, and tryptophan hydroxylases alkyl glycerol monoxygenase, which catalyzes the cleavage of alkyl glycerol ethers and nitric oxide synthase in the formation of nitric oxide. In addition to its coenzyme role, tetrahydrobiopterin has a direct effect on neurons, acting to stimulate dopamine release via a cAMP-dependent protein kinase and a calcium channel (Koshimura et al., 2000). 

The pterin-dependent oxygenases, typified by the aryl amino acid hydroxylases, are a small family of closely related enzymes, which are essential to mammalian physiology. This class of metalloenzymes employs tetrahydrobiopterin (BH4) as a two-electron donating cofactor for the activation of O2. Members of this class include phenylalanine (PheH), tyrosine (TyrH) and tryptophan (TrpH) hydroxylases, which effect regiospecific aromatic hydroxylations of the namesake amino acids. 

Kakoki M, Hirata Y, Hayakawa H, Suzuki E, Nagata D,Tojo A, Nishimatsu H, Nakanishi N, Hattori Y, Kikuchi K, NaganoT, Omata M Effects of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure. J Am Soc Nephrol 11 301 -9,... 

Individuals who cannot produce 5,6,7,8-tetrahydrobiopterin must be supplied with L-dopa and 5-hydroxy tryptophan, metabolic precursors to norepinephrine and serotonin. Why does supplying 5,6,7,8-tetrahydrobiopterin have no effect ... 

The combination of interferon-y plus TNF-a or interleukin-1 8 (IL-IjS), on the other hand, has been shown to paradoxically enhance endothelial NOS activity, despite a concurrent decrease in NOS mRNA, an effect that may be accounted for by increased endogenous tetrahydrobiopterin levels (Rosenkranz-Weiss a/., 1994). 

Unfortunately, tetrahydrobiopterin does not traverse the blood-brain barrier readily therefore, exogenous administration is not likely to be effective. At present L-dopa and 5-hydroxytryptophan administration are recommended to circumvent the block in neurotransmitter synthesis (Steinfeld et al., 2002 Muntau et al., 2002). 

Christ SE, et al. The effects of tetrahydrobiopterin (BH4) treatment on brain function in individuals with phenylketonuria. Neuroimage CUn. 2013 3 539 7. 

Humphrey M, et al. Effect of tetrahydrobiopterin on Phe/Tyr ratios and variation in Phe levels in tetrahydrobiopterin responsive PKU patients. Mol Genet Metab. 2011 104(l-2) 89-92. 

Abu-Soud HM, Gachhui R, Raushel FM, Stuehr DJ (1997) The ferrous-dioxy complex of neuronal nitric oxide synthase. Divergent effects of i-arginine and tetrahydrobiopterin on its stability. J Biol Chem 272 17349-17353... 

The inhibitory effect of aluminium on in vitro tetrahydrobiopterin synthesis in brain preparations may be due to competition with the magnesium re-... 

Other neurochemical studies have not been carried out in lead-exposed humans. It is difficult to measure neurochemical functions in vivo without recourse to such techniques as cerebrospinal fluid collection. However, the reported effects of lead exposure in rodents on plasma concentrations of prolactin (Govoni et al., 1978) and other pituitary hormones (Petrusz et al., 1979), and tetrahydrobiopterin (Leeming and Blair, 1980 McIntosh et al., 1982) would suggest that similar studies in humans might be considered. 

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