NUTRITIONAL REGULATION OF CYSTEINE DIOXYGENASE

半胱氨酸双加氧酶(CDO，EC 1.13.11.20)活性异常或缺乏，已被认为存在于各种非神经系统和神经系统疾病患者中。CDO活性低可能会导致问题，要么是因为半胱氨酸分解代谢产物硫酸盐(或牛磺酸)供应不足，而半胱氨酸分解代谢产物是各种目的，包括II相结合反应，要么是因为半胱氨酸或有毒代谢物的积累。我们已经确定CDO是参与调节半胱氨酸分解代谢的主要肝酶。监管反应强劲，在喂食低蛋白饲料的动物肝脏中几乎检测不到CDO活性，而在喂食高蛋白质或含硫氨基酸的饲料的大鼠中，CDO活性增加了170倍。长期目标是进一步阐明CDO调节的分子机制，并了解CDO的遗传或其他损伤在类风湿性关节炎等疾病的病因中的可能贡献。建议的研究包括(1)两种CDO亚型的特征；(2)研究CDO在非肝脏组织(脑、肾和肺)中的表达和半胱氨酸的调节，以此作为了解半胱氨酸代谢与某些与衰老相关的神经和非神经疾病的发生和进展的关系的步骤；(3)评估CDO水平增加的机制--半胱氨酸存在时，CDO蛋白的翻译速率增加或CDO蛋白的稳定性增加，如果合适的话，检查可能形成CDO的另一种加工的mRNA转录本；(4)评估正常大鼠组织半胱氨酸浓度与CDO水平的关系。实验将包括对大鼠的饮食治疗和评估饮食对不同组织中CDO表达的影响，研究参与调控CDO丰度的分子机制，以及从这些大鼠或原代培养的肝细胞中分离出CDO蛋白和CDO mRNA的特征。

Abnormal or deficient cysteine dioxygenase (CDO, EC 1.13.11.20) activity has been claimed to be seen in individuals with a variety of diseases, both non-neurological and neurological. Low CDO activity may result in problems, either because of insufficient supply of sulfate (or taurine) as products of cysteine catabolism that are needed for a variety of purposes including phase II conjugation reactions or because of accumulation of cysteine or toxic metabolites. We have identified CDO as the major hepatic enzyme involved in regulation of cysteine catabolism. The regulatory response is robust, with CDO activity being barely detectable in liver of animals fed low protein diets and increasing up to 170-fold in rats fed diets containing high levels of protein or sulfur amino acids. The long-term objective is to further elucidate the molecular mechanisms involved in the regulation of CDO and to understand the possible contribution of genetic or other impairments in CDO in the etiology of diseases such as rheumatoid arthritis. Proposed studies include (1) the characterization of the two CDO isoforms; (2) studies of CDO expression and regulation by cysteine in nonhepatic tissues (brain, kidney, and lung) as a step in understanding the relation of cysteine metabolism to the development and progression of certain neurological and nonneurological diseases associated with aging; (3) assessment of the mechanism by which CDO levels are increased -- an increased rate of mRNA translation or an increased stability of CDO protein in the presence of cysteine, and, if appropriate, examination of the possible formation of an alternatively processed mRNA transcript for CDO; and (4) assessment of the relationship of tissue cysteine concentration to CDO levels in intact rats. Experiments will involve dietary treatments of rats and assessment of the effects of diet on CDO expression in various tissues, studies of the molecular mechanisms involved in regulation of CDO abundance, and characterization of CDO protein and CDO mRNA isolated from these rats or from hepatocytes in primary culture.