Functional interactions between GTP cyclohydrolase I and tyrosine hydroxylase in Drosophila
Functional interactions between GTP cyclohydrolase I and tyrosine hydroxylase in Drosophila
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DOI：
10.3109/01677060009083474
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发表时间：
2000-01-01
影响因子：
1.9
通讯作者：
O'Donnell, J
中科院分区：
文献类型：
--
作者：
Krishnakumar, S;Burton, D;O'Donnell, J
酪氨酸羟化酶需要调节辅因子，四氢生物蝶呤，用于儿茶酚胺的生物合成。由于鸟苷三磷酸环化水解酶I是合成这种辅因子的限速酶，因此它在儿茶酚胺生产中具有关键作用。我们发现，GTP环化水解酶和酪氨酸羟化酶（TH）的共同定位在果蝇中枢神经系统。在打孔位点，编码GTP环化水解酶的突变，减少TH活性;此外，辅因子粗提取物不能完全挽救这种活动在所有突变株。TH活性的降低和不能用添加的辅因子来增加它不是由于TH蛋白的损失或减少的产生。我们发现，TH共免疫沉淀与GTP环化水解酶的野生型头部提取物与抗GTP环化水解酶抗体孵育时。我们认为，TH的调节，其辅因子可能需要其协会与GTP环化水解酶，和GTP环化水解酶的能力与TH及其在四氢生物蝶呤合成的作用可能是这种酶的可分离的功能。这些结果对了解儿茶酚胺相关的神经疾病和设计基因治疗策略具有重要意义。
Tyrosine hydroxylase requires the regulatory cofactor, tetrahydrobiopterin, for catecholamine biosynthesis. Because guanosine triphosphate cyclohydrolase I is the rate limiting enzyme for the synthesis of this cofactor, it has a key role in catecholamine production. We show that GTP cyclohydrolase and tyrosine hydroxylase (TH) are co-localized in the Drosophila central nervous system. Mutations in the Punch locus, which encodes GTP cyclohydrolase, reduce TH activity; addition of cofactor to crude extracts could not fully rescue this activity in all mutant strains. The decrease in TH activity and the inability to increase it with added cofactor is not due to loss or decreased production of TH protein. We found that TH co-immunoprecipitated with GTP cyclohydrolase when wild type head extracts were incubated with anti-GTP cyclohydrolase antibody. We suggest that regulation of TH by its cofactor may require its association with GTP cyclohydrolase, and that the ability of GTP cyclohydrolase to associate with TH and its role in tetrahydrobiopterin synthesis may be separable functions of this enzyme. These results have important implications for understanding catecholamine-related neural diseases and designing strategies for gene therapy.