GTP CYCLOHYDROLASE IN TISSUES

组织中的 GTP 环水解酶

• 批准号: 3405910
• 负责人: RONG-SEN SHEN
• 金额: $ 10.28万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3405910
• 关键词: affinity chromatography; brain; dopamine; enzyme complex; enzyme structure; folate; gel electrophoresis; gel filtration chromatography; guanosine triphosphate; high performance liquid chromatography; human tissue; hydrolase; liver; neurotransmitter metabolism; pteridines; tranquilizer

GTP cyclohydrolase (GTP-CH) catalyzes the initial and regulatory step of tetrahydrobiopterin (BH-4) synthesis. BH-4 is the essential cofactor for the hydroxylation of phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp). It may regulate Phe hydroxylase activity by acting as a negative effector of its activation. In neurons, BH-4 may be responsible for the phosphorylation of Tyr and Trp hydroxylases, which enhances their activities. Induction of GTP-CH followed by elevation of BH-4 level and enhancement of Tyr hydroxylase activity have been reported. Just as Tyr hydroxylase is a marker for dopamine, GTP-CH is a marker for BH-4. BH-4 deficiency may reflect a defect of this enzyme and/or one of its biosynthetic enzymes. Variant forms of hyperphenylalaninemia have been found to be caused by a deficiency of BH-4. Reduced levels of BH-4 in cerebrospinal fluids from patients with Parkinson's disease, torsion dystonias, senile dementia of Alzheimer type, Steel-Richardson syndrome, and Huntington's chorea have also been reported. Monotherapy with BH-4 has proven successful in some patients with these disorders. Mammalian GTP-CH may be an aggregate of enzymes, but the enzyme complex itself has not yet been systematically studied. The research plan proposes the following studies: 1. Purify GTP-CH to homogeneity from liver and brain of rat and human. 2. Study the enzyme properties and protein structure of the multiple forms of GTP-CH. 3. Investigate the in vitro and in vivo regulation of GTP-CH activity by endogenous and exogenous compounds. This study should generate important basic information on the chemistry and function of mammalian GTP-CH, and the co-regulation of GTP-CH activity and BH-4 levels in rat brain. This information should also shed light on the role of GTP-CH and/or BH-4 in the development and treatment of monoamine-related neurological and psychiatric disorders.

GTP环化水解酶（GTP-CH）催化的初始和调节步骤， 四氢生物蝶呤（BH-4）的合成。 BH-4是 苯丙氨酸（Phe）、酪氨酸（Tyr）和色氨酸的羟基化 （Trp）。 它可能通过作为一种负调节因子来调节苯丙氨酸羟化酶的活性。 其激活效应。 在神经元中，BH-4可能负责 Tyr和Trp羟化酶的磷酸化，这增强了它们的 活动 诱导GTP-CH，然后升高BH-4水平， 已经报道了Tyr羟化酶活性的增强。 正如Tyr羟化酶是多巴胺的标志物，GTP-CH是多巴胺的标志物。 BH-4 BH-4缺乏可能反映了这种酶的缺陷和/或以下之一： 它的生物合成酶。 高苯丙氨酸血症的变异形式已被 发现是由BH-4缺乏引起的。 降低BH-4水平， 帕金森病患者的脑脊液，扭转 肌张力障碍，阿尔茨海默型老年痴呆，Steel-Richardson综合征， 和亨廷顿舞蹈病也有报道。 BH-4单药治疗 在一些患有这些疾病的患者中证明是成功的。 哺乳动物GTP-CH可能是一种酶的聚集体，但酶复合物 它本身还没有得到系统的研究。 研究计划提出， 以下研究： 1.从大鼠和人的肝和脑中纯化GTP-CH至均一。 2.研究多种形式的酶性质和蛋白质结构 关于GTP-CH 3.研究GTP-CH活性的体外和体内调节， 内源和外源化合物。 这项研究应产生重要的基本信息的化学和 哺乳动物GTP-CH的功能，以及GTP-CH活性和 大鼠脑中BH-4水平。 这一信息也应该阐明 GTP-CH和/或BH-4在发展和治疗 单胺相关的神经和精神障碍。