DIHYDROPTERIDINE REDUCTASE IN HUMAN TISSUES

该项目的长期目标是为以下方面奠定基础： 二氢蝶啶还原酶临床意义的探讨 （DHPR）单胺相关的神经和精神疾病。 这 酶，提供一种必需的辅因子（四氢生物蝶呤，或BH 4） 用于单胺合成中芳香族氨基酸的羟基化， 是大脑正常功能所必需的 DHPR缺陷或 BH 4合成的缺陷导致高苯丙氨酸血症的变体形式。 帕金森病患者脑脊液中BH 4水平降低 疾病，扭转肌张力障碍，阿尔茨海默病，斯蒂尔-理查森综合征， 和亨廷顿舞蹈病也有报道。 的临床研究 然而，由于缺乏关于酶的信息， 监管控制其活动，特别是其结构和 与其内源性和外源性抑制剂的功能关系。 未来临床研究的进展将取决于以下方面的基础研究： DHPR在酪氨酸羟化和单胺调节中的作用 中枢神经系统的合成。 我们建议开始我们的研究 通过比较人脑DHPR和多种形式的酶， 存在于人体血小板和肝脏中 然后我们会调查 通过药理学试剂和内源性调节DHPR活性 大鼠中的因子，使用大鼠脑突触体的体外模型系统 纹状体 这些实验系统将允许选择性抑制 研究以确定酪氨酸羟化酶或DHPR的抑制 活性影响羟基化系统和儿茶酚胺合成。 如果 我们发现大脑和血小板的DHPR是相同的，我们将能够在 晚些时候使用血小板样本筛查非活性或变异 人类中的酶形式，包括患有 神经和精神疾病。

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.