BIOSYNTHESIS OF TETRAHYDROBIOPTERIN IN DROSOPHILA MELANOGASTER

四氢生物蝶呤(H4B)合成的遗传变异已被 与几种人类神经疾病有关，如非典型 苯丙酮尿症、帕金森氏症和阿尔茨海默病。这个 H4B对这些过程的重要性在于它作为一种必不可少的 酪氨酸和色氨酸羟基酶的辅因子，参与 儿茶酚胺和5-羟色胺的合成。BH4也是 一氧化氮合酶在合成一氧化氮过程中所需的 一种强大的细胞信号分子，参与控制 哺乳动物的血管扩张作用。BH4在真核生物中结构保守， 显然，这是其生物合成的途径。……的生物合成 BH4，在昆虫、老鼠和人类等各种生物中，最低限度 需要GTP环水解酶，1，丙酮酰-H4蝶呤还原酶 BH4的生物合成仍不清楚。建议的研究包括 果蝇丙酮酰化果蝇的分离纯化及生化特性 H4蝶呤还原酶。纯化的酶将用于多克隆的培养 抗血清。α-丙酮酰-H4pterin还原酶抗体将用于 分离编码该酶和其他生化产物的分子克隆 丙酮酰-H4pterin还原酶的定位等性质 在原地。一种分离丙酮酰的经典突变筛选- H4pterin还原酶突变体被建议作为独立本科生 学生项目。尽管人类感染H4B病毒的几个“先天错误” 生物合成存在(GTP)环水解酶1、丙酮酰-H4蝶呤合成酶、 二氢蝶呤还原酶)没有已知的丙酮酰-H4蝶呤还原酶 突变。果蝇是唯一一种有直接策略的生物 由于丙酮酰-H4pterin的参与，获得了这样一个突变体 导致眼色素合成的途径中的还原酶。长期目标 这些研究的目的是为了有助于对航站楼的理解 果蝇和其他高等生物中BH4生物合成的步骤。

Genetic variations in the synthesis of tetrahydrobiopterin (H4B) have been associated with several human neurological disorders such as atypical phenylketonuria, Parkinson's disease, and Alzheimer's disease. The importance of H4B to these processes is found in its role as an essential cofactor for tyrosine and tryptophan hydroxylase, enzymes involved in the synthesis of catecholamines and serotonin, respectively. BH4 is also required by nitric oxide synthase in the synthesis of nitric oxide, a potent cell-signaling molecule which is involved in the control of vasodilation in mammals. BH4 is structurally conserved among eukaryotes, as is apparently the pathway for its biosynthesis. The biosynthesis of BH4, in organisms as diverse as insects, rats and humans, minimally requires GTP cyclohydrolase, 1, pyruvoyl-H4pterin reductase ina the biosynthesis of BH4 remains unclear. The proposed research includes the purification and biochemical characterization of the Drosophila pyruvoyl- H4pterin reductase. The purified enzyme will be used to raise polyclonal antisera. The alpha-pyruvoyl-H4pterin reductase antibody will be used to isolate a molecular clone encoding for the enzyme and in other biochemical characterizations such as the localization of pyruvoyl-H4pterin reductase in situ. A classical mutant screen for the isolation of a pyruvoyl- H4pterin reductase mutant is proposed as an independent undergraduate student project. Although several human "in born errors" of H4B biosynthesis exist (GTP) cyclohydrolase 1, pyruvoyl-H4pterin synthase, dihydropteridine reductase) there is no known pyruvoyl-H4pterin reductase mutation. Drosophila is the only organism where there is a direct strategy for obtaining such a mutant, due to the involvement of pyruvoyl-H4pterin reductase in pathways leading to eye pigment synthesis. The long term goal of these studies is to contribute to the understanding of the terminal steps of BH4 biosynthesis in Drosophila and other higher organisms.