Nagatsu T, Ichinose H
Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.
Mol Neurobiol. 1999 Feb;19(1):79-96. doi: 10.1007/BF02741379.
Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin reductase (SPD). GCH is the rate-limiting enzyme. BH4 is a cofactor for three pteridine-requiring monooxygenases that hydroxylate aromatic L-amino acids, i.e., tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and phenylalanine hydroxylase (PAH), as well as for nitric oxide synthase (NOS). The intracellular concentrations of BH4, which are mainly determined by GCH activity, may regulate the activity of TH (an enzyme-synthesizing catecholamines from tyrosine), TPH (an enzyme-synthesizing serotonin and melatonin from tryptophan), PAH (an enzyme required for complete degradation of phenylalanine to tyrosine, finally to CO2 + H2O), and also the activity of NOS (an enzyme forming NO from arginine), Dominantly inherited hereditary progressive dystonia (HPD), also termed DOPA-responsive dystonia (DRD) or Segawa's disease, is a dopamine deficiency in the nigrostriatal dopamine neurons, and is caused by mutations of one allele of the GCH gene. GCH activity and BH4 concentrations in HPD/DRD are estimated to be 2-20% of the normal value. By contrast, recessively inherited GCH deficiency is caused by mutations of both alleles of the GCH gene, and the GCH activity and BH4 concentrations are undetectable. The phenotypes of recessive GCH deficiency are severe and complex, such as hyperphenylalaninemia, muscle hypotonia, epilepsy, and fever episode, and may be caused by deficiencies of various neurotransmitters, including dopamine, norepinephrine, serotonin, and NO. The biosynthesis of dopamine, norepinephrine, epinephrine, serotonin, melatonin, and probably NO by individual pteridine-requiring enzymes may be differentially regulated by the intracellular concentration of BH4, which is mainly determined by GCH activity. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. The nigrostriatal dopamine neurons may be most susceptible to a partial decrease in BH4, causing dopamine deficiency in the striatum and the HPD/DRD phenotype.
四氢生物蝶呤（BH4）由鸟苷三磷酸（GTP）经GTP环化水解酶I（GCH）、6-丙酮酸四氢蝶呤合酶（PTS）和蝶呤还原酶（SPD）合成。GCH是限速酶。BH4是三种需要蝶呤的单加氧酶的辅因子，这些酶可使芳香族L-氨基酸羟基化，即酪氨酸羟化酶（TH）、色氨酸羟化酶（TPH）和苯丙氨酸羟化酶（PAH），以及一氧化氮合酶（NOS）。主要由GCH活性决定的细胞内BH4浓度可能调节TH（一种从酪氨酸合成儿茶酚胺的酶）、TPH（一种从色氨酸合成血清素和褪黑素的酶）、PAH（一种将苯丙氨酸完全降解为酪氨酸最终生成二氧化碳和水所需的酶）的活性，以及NOS（一种从精氨酸生成NO的酶）的活性。显性遗传性进行性肌张力障碍（HPD），也称为多巴反应性肌张力障碍（DRD）或Segawa病，是黑质纹状体多巴胺神经元中的多巴胺缺乏症，由GCH基因的一个等位基因突变引起。HPD/DRD中的GCH活性和BH4浓度估计为正常值的2% - 20%。相比之下，隐性遗传性GCH缺乏症由GCH基因的两个等位基因突变引起，且无法检测到GCH活性和BH4浓度。隐性GCH缺乏症的表型严重且复杂，如高苯丙氨酸血症、肌张力减退、癫痫和发热发作，可能由多种神经递质缺乏引起，包括多巴胺、去甲肾上腺素、血清素和NO。由个别需要蝶呤的酶合成多巴胺、去甲肾上腺素、肾上腺素、血清素、褪黑素以及可能的NO的过程可能受细胞内BH4浓度的差异调节，而细胞内BH4浓度主要由GCH活性决定。不同组多巴胺神经元中的多巴胺生物合成可能受TH活性的差异调节，这取决于细胞内BH4浓度和GCH活性。黑质纹状体多巴胺神经元可能对BH4的部分降低最为敏感，导致纹状体多巴胺缺乏和HPD/DRD表型。
