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GTP CYCLOHYDROLASE IN TISSUES

组织中的 GTP 环水解酶

基本信息

批准号：
3405911
负责人：
RONG-SEN SHEN
金额：
$ 9.56万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-09-01 至 1990-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3405911
关键词：
affinity chromatography brain dopamine enzyme complex enzyme mechanism enzyme structure folate gel electrophoresis gel filtration chromatography guanosine triphosphate high performance liquid chromatography human tissue hydrolase laboratory rat liver neurotransmitter metabolism pteridines tranquilizer

项目摘要

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）。它可能通过负作用调节Phe羟化酶活性其激活效应。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。