Regulation of Homocysteine-dependent Redox Homeostasis

同型半胱氨酸依赖性氧化还原稳态的调节

• 批准号: 7454732
• 负责人: RUMA V BANERJEE
• 金额: $ 25.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-11 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454732
• 关键词: Address; Affect; Aging; Alleles; Alzheimer' s Disease; Amino Acids; Anabolism; Antioxidants; Apoptosis; Arthritis; Biological; Buffers; Cardiovascular Diseases; Cells; Cobalamin; Colon Carcinoma; Complex; Cultured Cells; Cystathionine; Cystathionine beta-Synthase; Cysteine; Disease; Disruption; Drug or chemical Tissue Distribution; Enzymes; Equilibrium; Etiology; Eukaryota; Eukaryotic Cell; Flavoproteins; Genetic Polymorphism; Germ-Line Mutation; Glutathione; Hemeproteins; Homeostasis; Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Inherited; Internal Ribosome Entry Site; Kinetics; Knockout Mice; Ligase; Link; Liver; Malignant Neoplasms; Messenger RNA; Metabolic; Metabolism; Methionine; Molecular; Mus; Mutation; NADP; Neural Tube Defects; Numbers; Open Reading Frames; Organ; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Parkinson Disease; Pathway interactions; Physiological Processes; Predisposition; Property; Pyridoxal Phosphate; Reagent; Regulation; Role; Route; Stress; Study models; Sulfhydryl Compounds; Sulfur; Translational Regulation; Up-Regulation; Variant; Xenobiotics; Zonula Adherens; base; betaine-homocysteine methyltransferase; glutathione synthase; insight; methionine synthase reductase; mouse model; mutant; response; transmethylation

DESCRIPTION (provided by applicant): Perturbations of redox homeostasis incurred by oxidative stress appear to be a common thread connecting the etiologies of various complex and multifactorial diseases, such as cardiovascular diseases, Parkinson's disease, Alzheimer's disease, arthritis and some cancers. Glutathione is a key component of the intracellular arsenal of antioxidants in eukaryotes, and the limiting reagent in its synthesis is believed to cysteine. The transsulfuration pathway which converts homocysteine to cysteine is a quantitatively significant contributor to the intracellular cysteine pool in the liver and -50 percent of the cysteine in glutathione is derived via this pathway. Homocysteine is a sulfur containing amino acid whose elevated levels are correlated with a number of multifactorial diseases such as cardiovascular diseases, neural tube defects and Alzheimer's disease. However, intracellular regulation of this amino acid and of the metabolic link to the major cellular redox buffer pool of glutathione are poorly understood. This proposal focuses on three key loci important in regulation of homocysteine concentrations: methionine synthase, methionine synthase reductase and cystathionine beta-synthase. Mutations in each of these enzymes is correlated with hereditary hyperhomocystenemia which is inherited as an autosomal recessive disorder. Using a combination of biophysical, cell biological and mouse model studies for cystathionine beta-synthase deficiency, we will; (i) characterize how polymorphic variations and hereditary mutations in methionine synthase reductase influence redox activation of methionine synthase-dependent transmethyiation of homocysteine, (ii) elucidate the mechanism of translational regulation of methionine synthase and (iii) elucidate the mechanism of redox regulation of homocysteine metabolism and its influence on glutathione homeostasis. These studies will provide important insights into multiple levels of regulation of homocysteine metabolism and will assess the effects of modulating the transsulfuration pathway on glutathione-dependent antioxidant defense in cell culture and in mice.

描述（由申请人提供）：氧化应激引起的氧化还原稳态的扰动似乎是连接各种复杂和多因素疾病的病因，例如心血管疾病，例如心血管疾病，帕金森氏病，阿尔茨海默氏病，阿尔茨海默氏病，关节炎和某些癌症。谷胱甘肽是真核生物中抗氧化剂细胞内砷的关键组成部分，其合成中的极限试剂被认为是半胱氨酸。将同型半胱氨酸转换为半胱氨酸的转硫途径是肝内细胞内半胱氨酸池的定量显着贡献，而谷胱甘肽中半胱氨酸的-50％是通过该途径得出的。同型半胱氨酸是一种含有氨基酸的硫，其升高水平与多种多因素疾病（例如心血管疾病，神经管缺陷和阿尔茨海默氏病）相关。然而，对谷胱甘肽的主要细胞氧化还原缓冲库的代谢连接的细胞内调节知之甚少。该提议着重于在调节同型半胱氨酸浓度的三个关键基因座上：蛋氨酸合酶，蛋氨酸合酶还原酶和胱氨酰β-合成蛋白合成酶。这些酶的突变与遗传性高粒细胞核相关，后者遗传为常染色体隐性障碍。使用生物物理，细胞生物学和小鼠模型研究的结合，用于胱淀粉β-合酶缺乏症，我们将； （i）表征蛋氨酸合酶还原酶中的多态性变异和遗传突变如何影响甲二氨氨酸合酶依赖性同型半胱氨酸的氧化还原激活，（ii）阐明了甲硫氨酸合酶和（iii）的转化机制的机制稳态。这些研究将为同型半胱氨酸代谢的多种水平调节提供重要的见解，并将评估调节经硫化途径对细胞培养和小鼠中谷胱甘肽依赖性抗氧化剂防御的影响。