GENE-NUTRIENT INTERACTIONS IN REDOX HOMEOSTASIS

氧化还原稳态中的基因-营养相互作用

• 批准号: 6447197
• 负责人: RUMA V BANERJEE
• 金额: $ 6.94万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6447197
• 关键词: acid aminoacid ligase; aldehyde /ketone oxidoreductase; aminoacid metabolism; biological models; chemical kinetics; chemical structure function; cystathionine beta synthase; environmental stressor; free radical oxygen; gene environment interaction; gene induction /repression; genetic regulation; genetically modified animals; glutathione; high performance liquid chromatography; homocysteine; laboratory mouse; liver cells; northern blottings; nutrient interaction; oxidation reduction reaction; oxidative stress; radiotracer; western blottings

DESCRIPTION (provided by applicant) There is a growing literature on the role of dietary and environmental modulators in the control of reactive oxygen species that are implicated in the etiology of multiple and complex diseases such as cardiovascular diseases, Alzheimer's disease, Parkinson's disease, arthritis, certain cancers as well as in aging and apoptosis. Glutathione is a key endogenous antioxidant that plays a major role in cellular defense against reactive oxygen species and xenobiotics. The biosynthesis of glutathione is comprised of: (1) the upstream trans-sulfuration pathway that provides an avenue for conversion of the essential amino acid, methionine, to cysteine, the limiting amino acid in glutathione synthesis; and (2) the downstream pathway representing the final 2 steps catalyzed by gamma-glutamyl-cysteine synthetase and glutathione synthetase. The upstream pathway is present only in tissues with the highest concentration of glutathione, whereas the downstream pathway is ubiquitous. Tissues lacking the upstream pathway depend on an exogenous supply of cysteine, and inter-organ transport of glutathione plays a key role in providing this nonessential amino acid to these cells. A number of vitamins (B6, B12 and folic acid) and cofactors (heme and Zn2+) converge at this metabolic focal point and could potentially affect glutathione synthesis and, therefore, cellular redox homeostasis. The research design of this project is guided by 3 specific aims: (1) to address how regulation of the up- and downstream pathways is coordinated by using a mouse knockout model for cystathionine beta-synthase, the first enzyme in the trans-sulfuration pathway. These studies will be a prelude to characterizing the effects of macro- (methionine, cysteine) and micronutrients (B6, B12 and folate) on modulating glutathione pools in the 3 genetic backgrounds (+/+, +/-and -/- cbs); (2) to elucidate the relative efficacies of the different genotypes in handling oxidative and xenobiotic challenges; and (3) to initiate studies to elucidate the molecular mechanism of redox regulation of gamma-glutamyl- cysteine synthetase, the rate-limiting enzyme in glutathione biosynthesis, by focusing on the properties of the regulatory subunit that the principal investigator has discovered is a member of the aldo-keto reductase superfamily.

描述（由申请人提供） 关于饮食和环境的作用的文献越来越多 控制活性氧的调节剂涉及 心血管疾病等多种复杂疾病的病因学， 阿尔茨海默病、帕金森病、关节炎和某些癌症 如衰老和细胞凋亡。 谷胱甘肽是一种重要的内源性抗氧化剂， 在细胞防御活性氧中发挥重要作用 异生素。 谷胱甘肽的生物合成包括：（1） 上游反式硫化途径，提供了转化的途径 必需氨基酸蛋氨酸到半胱氨酸，限制性氨基酸 谷胱甘肽合成； (2)代表最终2的下游路径 γ-谷氨酰半胱氨酸合成酶和谷胱甘肽催化的步骤 合成酶。 上游途径仅存在于具有最高的组织中 谷胱甘肽的浓度，而下游途径是普遍存在的。 缺乏上游途径的组织依赖于外源供应 半胱氨酸和谷胱甘肽的器官间运输起着关键作用 为这些细胞提供这种非必需氨基酸。 多种维生素 （B6、B12 和叶酸）和辅助因子（血红素和 Zn2+）在此汇聚 代谢焦点，可能会影响谷胱甘肽的合成， 因此，细胞氧化还原稳态。 本项目的研究设计是 以 3 个具体目标为指导：(1) 解决如何监管向上和向下的问题 通过使用小鼠敲除模型来协调下游途径 胱硫醚β-合酶，反式硫化过程中的第一个酶 途径。 这些研究将成为表征影响的前奏 大量营养素（蛋氨酸、半胱氨酸）和微量营养素（B6、B12 和叶酸） 调节 3 种遗传背景（+/+、+/- 和 -/- 哥伦比亚广播公司）； (2) 阐明不同基因型的相对功效 应对氧化和外源性挑战； (3) 启动研究 阐明γ-谷氨酰-氧化还原调节的分子机制 半胱氨酸合成酶，谷胱甘肽生物合成中的限速酶， 重点关注主体监管子单元的属性 研究人员发现它是醛酮还原酶的成员 超家族。