GTP CYCLOHYDROLASE IN TISSUES

GTP环水解酶(GTP-CH)催化的起始和调节步骤 四氢生物蝶呤(BH-4)合成。BH-4是重要的辅因子 苯丙氨酸、酪氨酸和色氨酸的羟基化 (Trp)。它可能通过作为负离子调节Phe羟基酶的活性 其激活的效应器。在神经元中，BH-4可能负责 酪氨酸和色氨酸羟化酶的磷酸化，从而增强它们的 活动。GTP-CH诱导后BH-4水平升高 酪氨酸羟基酶活性的增强已有报道。 正如酪氨酸羟化酶是多巴胺的标志一样，GTP-CH也是多巴胺的标志 BH-4。BH-4缺乏可能反映了这种酶的缺陷和/或 它的生物合成酶。各种形式的高苯丙氨酸血症 被发现是由BH-4缺乏引起的。年BH-4水平降低 帕金森氏病患者脑脊液扭转 肌张力障碍、阿尔茨海默型老年性痴呆、斯蒂尔-理查森综合征、 亨廷顿舞蹈症也有报道。BH-4的单一疗法有 在一些患有这些疾病的患者中被证明是成功的。 哺乳动物的GTP-CH可能是酶的聚集体，但酶的复合体 其本身还没有得到系统的研究。研究计划提出 以下是研究： 1.从大鼠和人的肝脏和脑中分离纯化GTP-CH，得到均一的GTP-CH。 2.研究多种形式的酶性质和蛋白质结构 GTP-CH. 3.研究GTP-CH的体内外活性调节 内源化合物和外源化合物。 这项研究应该产生关于化学和化学的重要基本信息 哺乳动物GTP-CH的功能及其与GTP-CH活性的共同调节 大鼠脑组织中BH-4水平。这一信息也应该有助于揭示 GTP-CH和/或BH-4在糖尿病的发生和治疗中的作用 与单胺有关的神经和精神障碍。

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.