Citron B A, Kaufman S, Milstien S, Naylor E W, Greene C L, Davis M D
Laboratory of Neurochemistry, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892.
Am J Hum Genet. 1993 Sep;53(3):768-74.
Hyperphenylalaninemias represent a major class of inherited metabolic disorders. They are most often caused by mutations in the phenylalanine hydroxylase gene and, less frequently but with usually more serious consequences, in genes necessary for the synthesis and regeneration of the cofactor, tetrahydrobiopterin. This cofactor is absolutely required for all aromatic amino acid hydroxylations, and, recently, nitric oxide production from L-arginine has also been found to be dependent on tetrahydrobiopterin. Phenylalanine hydroxylase catalyzes a coupled reaction in which phenylalanine is converted to tyrosine and in which tetrahydrobiopterin is converted to the unstable carbinolamine, 4a-hydroxytetrahydrobiopterin. The enzyme, carbinolamine dehydratase, catalyzes the dehydration of the carbinolamine to quinonoid dihydropterin. A decreased rate of dehydration of this compound has been hypothesized to be responsible for the production of 7-biopterin found in certain mildly hyperphenylalaninemic individuals. We have now identified nonsense and missense mutations in the 4a-carbinolamine dehydratase gene in a hyperphenylalaninemic child who excretes large amounts of 7-biopterin. This finding is consistent with the role of the carbinolamine dehydratase in the phenylalanine hydroxylation reaction. Together with previously identified inherited disorders in phenylalanine hydroxylase and dihydropteridine reductase, there are now identified mutations in the three enzymes involved in the phenylalanine hydroxylation system. In addition, the genetics of this system may have broader implications, since the product of the dehydratase gene has previously been shown to play an additional role (as dimerization cofactor for hepatocyte nuclear factor-1 alpha) in the regulation of transcription, through interaction with hepatocyte nuclear factor-1 alpha.
高苯丙氨酸血症是一大类遗传性代谢紊乱疾病。它们最常见的病因是苯丙氨酸羟化酶基因突变，较少见但通常后果更严重的病因是四氢生物蝶呤（该辅助因子合成与再生所必需的基因）突变。所有芳香族氨基酸羟化反应都绝对需要这种辅助因子，最近还发现，从L-精氨酸生成一氧化氮也依赖于四氢生物蝶呤。苯丙氨酸羟化酶催化一个偶联反应，其中苯丙氨酸转化为酪氨酸，四氢生物蝶呤转化为不稳定的氨基甲醇，即4a-羟基四氢生物蝶呤。氨基甲醇脱水酶催化氨基甲醇脱水生成醌型二氢蝶呤。据推测，该化合物脱水速率降低是某些轻度高苯丙氨酸血症个体中7-生物蝶呤产生的原因。我们现已在一名排泄大量7-生物蝶呤的高苯丙氨酸血症儿童中，鉴定出4a-氨基甲醇脱水酶基因中的无义突变和错义突变。这一发现与氨基甲醇脱水酶在苯丙氨酸羟化反应中的作用一致。连同先前鉴定出的苯丙氨酸羟化酶和二氢蝶呤还原酶的遗传性疾病，现在已确定了参与苯丙氨酸羟化系统的三种酶中的突变。此外，该系统的遗传学可能具有更广泛的意义，因为脱水酶基因的产物先前已被证明通过与肝细胞核因子-1α相互作用，在转录调控中发挥额外作用（作为肝细胞核因子-1α的二聚化辅助因子）。
