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Tetrahydrobiopterin deficiency and brain nitric oxide synthase in the hph1 mouse
Author(s) -
Brand M. P.,
Heales S. J. R.,
Land J. M.,
Clark J. B.
Publication year - 1995
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/bf00711370
Subject(s) - tetrahydrobiopterin , nitric oxide synthase , biopterin , nitric oxide , endocrinology , medicine , arginine , chemistry , gtp cyclohydrolase i , cofactor , citrulline , nos1 , biochemistry , enzyme , amino acid , biology
Summary Tetrahydrobiopterin (BH 4 ) 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 BH 4 metabolism lead to hyperphenylalaninaemia and impaired catecholamine and serotonin turnover. The effects of BH 4 deficiency on brain nitric oxide (NO) metabolism are not known. In this study we have used the hph‐1 mouse, which displays GTP cyclohydrolase deficiency, to study the effects of BH 4 deficiency on brain NOS. In the presence of exogenous BH 4 , NOS specific activity was virtually identical in the control and hph‐1 preparations. However, omission of BH 4 from the reaction buffer led to a significant 20% loss of activity in the hph‐1 preparations only. The K m for arginine was virtually identical for the control and hph‐1 NOS when BH 4 was present in the reaction buffer. In the absence of cofactor, the K m for arginine was 3‐fold greater for control and 5‐fold greater for hph‐1 preparations. It is concluded that (a) BH 4 does not regulate the intracellular concentration of brain NOS; (b) less binding of BH 4 to NOS occurs in BH 4 deficiency states; (c) BH 4 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 BH 4 deficiency states. Since, in the presence of suboptimal concentrations of BH 4 or arginine, NOS may additionally form oxygen free‐radicals, it is postulated that in severe BH 4 deficiency states NO formation is impaired and the central nervous system is subjected to increased oxidative stress.