Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck A-6020, Austria.
Biochem J. 2011 Sep 15;438(3):397-414. doi: 10.1042/BJ20110293.
BH4 (6R-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, including four aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and three NOS (NO synthase) isoenzymes. Consequently, BH4 is present in probably every cell or tissue of higher organisms and plays a key role in a number of biological processes and pathological states associated with monoamine neurotransmitter formation, cardiovascular and endothelial dysfunction, the immune response and pain sensitivity. BH4 is formed de novo from GTP via a sequence of three enzymatic steps carried out by GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. An alternative or salvage pathway involves dihydrofolate reductase and may play an essential role in peripheral tissues. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase, except for NOSs, in which the BH4 cofactor undergoes a one-electron redox cycle without the need for additional regeneration enzymes. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I. BH4 biosynthesis is controlled in mammals by hormones and cytokines. BH4 deficiency due to autosomal recessive mutations in all enzymes, except for sepiapterin reductase, has been described as a cause of hyperphenylalaninaemia. A major contributor to vascular dysfunction associated with hypertension, ischaemic reperfusion injury, diabetes and others, appears to be an effect of oxidized BH4, which leads to an increased formation of oxygen-derived radicals instead of NO by decoupled NOS. Furthermore, several neurological diseases have been suggested to be a consequence of restricted cofactor availability, and oral cofactor replacement therapy to stabilize mutant phenylalanine hydroxylase in the BH4-responsive type of hyperphenylalaninaemia has an advantageous effect on pathological phenylalanine levels in patients.
BH4（6R-L-erythro-5,6,7,8-四氢生物蝶呤）是一组酶的必需辅因子，这些酶在代谢中具有中心重要性，包括四种芳香族氨基酸羟化酶、烷基甘油单加氧酶和三种 NOS（一氧化氮合酶）同工酶。因此，BH4 存在于高等生物的几乎每一个细胞或组织中，并在许多与单胺神经递质形成、心血管和内皮功能障碍、免疫反应和疼痛敏感性相关的生物学过程和病理状态中发挥关键作用。BH4 是从头从 GTP 通过三个酶促步骤形成的，这三个步骤由 GTP 环化水解酶 I、6-丙酮酸四氢蝶呤合酶和蝶呤还原酶执行。替代或补救途径涉及二氢叶酸还原酶，并且可能在外周组织中发挥重要作用。辅因子的再生需要蝶呤-4a-甲醇胺脱水酶和二氢蝶啶还原酶，但 NOS 除外，在 NOS 中，BH4 辅因子不需要额外的再生酶即可进行单电子氧化还原循环。关于辅因子生物合成的调节，主要控制点是 GTP 环化水解酶 I。激素和细胞因子控制哺乳动物中的 BH4 生物合成。除蝶呤还原酶外，所有酶的常染色体隐性突变导致的 BH4 缺乏已被描述为高苯丙氨酸血症的原因。与高血压、缺血再灌注损伤、糖尿病等相关的血管功能障碍的一个主要原因似乎是氧化 BH4 的作用，这导致通过去偶合的 NOS 形成更多的氧衍生自由基而不是 NO。此外，几种神经疾病被认为是辅因子可用性受限的结果，并且口服辅因子替代疗法对 BH4 反应型高苯丙氨酸血症中突变型苯丙氨酸羟化酶的稳定对患者病理性苯丙氨酸水平具有有利影响。
