The Conversion of Phenylalanine to Tyrosine

我们已经证明了蝶呤和卡宾拉明 脱水酶(PCD)是一种双功能蛋白质。在细胞质中 细胞，它的功能是苯丙氨酸的基本成分 用于将苯丙氨酸转化为 酪氨酸。PCD和另一种酶二氢蝶啶 还原酶，功能是再生四氢生物蝶呤(BH4)， 羟化系统必需的辅酶。在…的核心 PCD细胞扮演着完全不同的角色：它与和 稳定HNF-1，一种基因转录因子，从而增强 这种蛋白质的转录活性。在这个角色中，PCD已经成为 称为DCoH。HNF-1参与了一个整体的转录 肝脏基因家族，包括编码蛋白质的基因，如 血清α-纤维蛋白原白蛋白和丙酮酸激酶。研究 令人惊讶的是，HNF-1基因敲除小鼠显示出 苯丙氨酸羟基酶是一种蛋白质，它的合成是 在HNF1的控制下。这些发现增加了 PCD/DCoH可能参与调节 苯丙氨酸羟基酶。我们已经证明了5‘侧翼 人类苯丙氨酸羟基酶基因的区域包含两个 与HNF-1结合的序列。当表达HNF-1和 PCD/DCoH基因导入中国仓鼠卵巢细胞 与含有适当5‘侧翼的质粒一起 苯丙氨酸羟基酶基因的区域，表达 苯丙氨酸羟基酶基因被高铁蛋白激活8倍 PCD/DCoH进一步扩增1.6倍。这些结果表明 PCD/DCoH确实在激活表达中起作用 苯丙氨酸羟基酶。我们计划研究是否还有其他 苯丙氨酸羟化体系的组成，如 苯丙氨酸和BH4可影响HNF-1和 PCD/DCoH刺激苯丙氨酸表达的研究 羟基酶。苯丙氨酸羟基酶在肝脏中含量更丰富 糖尿病大鼠。这一发现与其他观察结果一致。 表明苯丙氨酸的活性增加 有利于糖异生的条件下的羟基酶。我们有 现在证明了相反的是真的，即，提供动物 具有替代的饮食中的糖异生底物，如甘油 或果糖导致苯丙氨酸活性下降 羟基酶。这一下降似乎是次于下降的 BH4的浓度，这是由于 BH4的前体GTP的浓度。鉴于这一重要性 外周糖异生在为大脑提供其 基本燃料，肝脏苯丙氨酸代谢的这些方面可以 影响大脑的发育和功能。

We have shown that pterin carbinolamine dehydratase (PCD) is a dual function protein. In the cytoplasm of the cell, it functions as an essential component of the phenylalanine hydroxylating system that serves to convert phenylalanine to tyrosine. PCD, together with another enzyme, dihydropteridine reductase, functions to regenerate tetrahydrobiopterin (BH4), the essential coenzyme for the hydroxylating system. In the nucleus of the cell, PCD, plays a totally different role: it combines with and stabilizes HNF-1, a gene transcription factor, thereby enhancing the transcriptional activity of this protein. In this role, PCD has become known as DCoH. HNF-1 is involved in the transcription of a whole family of hepatic genes including those coding for proteins such as serum albumin of alpha-fibrocogen and pyruvate kinase. Studies with HNF-1 knockout mice have shown, surprisingly, that phenylalanine hydroxylase is one of the proteins whose synthesis is under the control of HNF 1. These findings raised the possibility that PCD/DCoH might be involved in regulating the synthesis of phenylalanine hydroxylase. We have shown that the 5'-flanking region of the human phenylalanine hydroxylase gene contains two sequences that bind HNF-1. When plasmids expressing HNF-1 and PCD/DCoH were transfected into Chinese hamster ovary cells together with a plasmid containing the appropriate 5' flanking region of the phenylalanine hydroxylase gene, the expression of the phenylalanine hydroxylase gene was stimulated 8-fold by the HNF plasmid and a further 1.6- fold by PCD/DCoH. These results show that PCD/DCoH do indeed play a role in activating the expression of phenylalanine hydroxylase. We plan to study whether other components of the phenylalanine hydroxylating system such as phenylalanine and BH4 can effect the ability of HNF-1 and PCD/DCoH to stimulate the expression of phenylalanine hydroxylase. Phenylalanine hydroxylase is more abundant in livers of diabetic rats. This finding is in accord with other observations showing that there is an increase in the activity of phenylalanine hydroxylase under conditions favoring gluconeogenesis. We have now shown that the converse is true, i.e., that providing the animal with alternative dietary gluconeogenic substrates such as glycerol or fructose leads to a decrease in the activity of phenylalanine hydroxylase. This decrease appears to be secondary to a decreased concentration of BH4 which is due to a decrease in the concentration of GTP, the precursor of BH4. Given the importance of peripheral gluconeogenesis in providing the brain with its essential fuel, these aspects of hepatic phenylalanine metabolism can affect the development and functioning of the brain.