DIHYDROPTERIDINE REDUCTASE IN HUMAN TISSUES

该项目的长期目标是为 二氢蝶呤还原酶的临床意义探讨 (DHPR)到与单胺相关的神经和精神障碍。这 酶，提供必需的辅因子(四氢生物蝶呤，或BH4) 在单胺合成中芳香族氨基酸的羟基化，是 是正常大脑功能所必需的。DHPR或a缺陷 BH4合成缺陷导致一种变种形式的高苯丙氨酸血症。 帕金森病患者脑脊液中BH4水平的降低 疾病，扭转肌张力障碍，阿尔茨海默病，斯蒂尔-理查森综合征， 亨廷顿舞蹈症也有报道。多发性骨髓瘤的临床研究 然而，由于缺乏关于该酶的信息，该酶一直受到阻碍 对其活动的监管，特别是对其结构和 与其内源性和外源性抑制物的功能关系。 未来临床研究的进展将取决于对 DHPR在酪氨酸羟化及单胺调节中的作用 中枢神经系统的合成。我们建议开始我们的研究 人脑DHPR与多种形式酶的比较 在人类的血小板和肝脏中发现。然后我们将调查 药物和内源性对DHPR活性的调节 大鼠脑突触小体体外模型系统--大鼠的因子 纹状体。这些实验系统将允许选择性抑制 确定酪氨酸羟化酶或DHPR抑制作用的研究 活性影响羟化系统和儿茶酚胺的合成。如果 我们发现大脑和血小板DHPR是相同的，我们将能够在一个 以后使用血小板样本进行不活跃或变异的筛查 人类人群中这种酶的形式，包括患有 神经和精神障碍。

The long-range goal of this project is to lay the groundwork for investigations of the clinical significance of dihydropteridine reductase (DHPR) to monoamine-related neurological and psychiatric disorders. This enzyme, which provides an essential cofactor (tetrahydrobiopterin, or BH4) for the hydroxylation of aromatic amino acids in monoamine synthesis, is known to be required for normal brain function. Deficiency in DHPR or a defect in BH4 synthesis causes a variant form of hyperphenylalaninemia. Reduced levels of BH4 in cerebrospinal fluids of patients with Parkinson's disease, torsion dystonia, Alzheimer's disease, Steel-Richardson syndrome, and Huntington's chorea have also been reported. Clinical studies of the enzyme have been hampered, however, by a lack of information about the regulatory control of its activity, especially its structural and functional relationships with its endogenous and exogenous inhibitors. Progress in future clinical studies will depend on basic investigations of the role of DHPR in tyrosine hydroxylation and the regulation of monoamine synthesis in the central nervous system. We propose to begin our studies with a comparison of human brain DHPR with the multiple forms of the enzyme found in human platelets and liver. Then we will investigate the regulation of DHPR activity by pharmacological agents and endogenous factors in rats, an in vitro model system using synaptosomes from rat brain striatum. These experimental systems will allow selective inhibition studies to determine how inhibition of either tyrosine hydroxylase or DHPR activity affects the hydroxylation system and catecholamine synthesis. If we find that brain and platelet DHPR are identical, we will be able at a later time to use platelet samples for screening for inactive or variant forms of the enzyme in the human population, including patients with neurological and psychiatric disorders.