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Tetrahydrobiopterin deficiency and brain nitric oxide synthase in the hph1 mouse

Tetrahydrobiopterin deficiency and brain nitric oxide synthase in the hph1 mouse,10.1007/BF00711370,Journal of Inherited Metabolic Disease,M. P. Brand

Tetrahydrobiopterin deficiency and brain nitric oxide synthase in the hph1 mouse   (Citations: 16)
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Tetrahydrobiopterin (BH4) is the cofactor for the aromatic amino acid monoxygenase group of enzymes and for all known isoforms of nitric oxide synthase (NOS). Inborn errors of BH4 metabolism lead to hyperphenylalaninaemia and impaired catecholamine and serotonin turnover. The effects of BH4 deficiency on brain nitric oxide (NO) metabolism are not known. In this study we have used thehph-1 mouse, which displays GTP cyclohydrolase deficiency, to study the effects of BH4 deficiency on brain NOS. In the presence of exogenous BH4, NOS specific activity was virtually identical in the control andhph-1 preparations. However, omission of BH4 from the reaction buffer led to a significant 20% loss of activity in thehph-1 preparations only. TheKm for arginine was virtually identical for the control andhph-1 NOS when BH4 was present in the reaction buffer. In the absence of cofactor, theKm for arginine was 3-fold greater for control and 5-fold greater forhph-1 preparations. It is concluded that (a) BH4 does not regulate the intracellular concentration of brain NOS; (b) less binding of BH4 to NOS occurs in BH4 deficiency states; (c) BH4 has a potent effect on the affinity of NOS for arginine; and (d) the availability of arginine for NOS activity may become severely limiting in BH4 deficiency states. Since, in the presence of suboptimal concentrations of BH4 or arginine, NOS may additionally form oxygen free-radicals, it is postulated that in severe BH4 deficiency states NO formation is impaired and the central nervous system is subjected to increased oxidative stress.
Journal: Journal of Inherited Metabolic Disease - J INHERIT METAB DIS , vol. 18, no. 1, pp. 33-39, 1995
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