STRUCTURAL STUDIES OF METHYL CYCLE ENZYMES

甲基环酶的结构研究

• 批准号: 6519235
• 负责人: Fusao None Takusagawa
• 金额: $ 19.93万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519235
• 关键词: Archaea; Clostridium; Escherichia coli; S adenosylmethionine; X ray crystallography; active sites; animal tissue; carbon nitrogen ligase; decarboxylases; enzyme inhibitors; enzyme mechanism; enzyme structure; enzyme substrate complex; homocysteine; methyl group; methyltransferase; peptidases; protein purification; tetrahydrofolates

Methylation reactions mediated by S-adenosylmethlonine (AdoMet) are increasingly being recognized as significant control factors in the regulation of a variety of cellular functions. Methylation of nucleic acids is known to have regulatory effects on DNA replication and transcription, and RNA translation. Protein methylation is involved in the regulation of a variety of metabolic processes such as bacterial chemotaxis, sperm mobility, release of neurotransmitters and possibly certain enzymatic activities. AdoMet is also the methyl donor for a vast number of small molecules (e.g., the biosynthesis and/or metabolism of various catechoiamine neurotransmitters). We have studied the structures and functions of enzymes involved in the methyl cycle reactions. A relatively large conformational change has been observed in the enzyme structures upon the binding of substrate or the leaving of product from the active site. In this grant period, Dr. Takusagawa will characterize the dynamic structures as well as the catalytic mechanisms of the following enzymes by X-ray diffraction method. S-adenosylm ethionine synthetase from human, rat, Methanococcus jannaschii, and E. coli. Glycline N-methyltransferase and guanidinoacetate methyltransferase from rat liver. S-adenosylhomocysteine hydrolase from rat liver and Alcaligenes faecalis. S-adenosylmethionine decarboxylase from E. coli. N10-formyl-tetrahydrofolate synthetase from Clostridium cylindrosporum. Serine dehydratase from rat liver. For a long-term objective, we would like to design specific inhibitors of these enzymes in order to develop chemotherapeutic agents using the active site geometries and the catalytic mechanisms of the enzymes gained in this project.

S-腺苷甲基氨酸（ADOMET）介导的甲基化反应 越来越多地被认为是重要的控制因素 调节多种细胞功能。核酸的甲基化为 已知对DNA复制和转录具有调节作用，RNA 翻译。蛋白甲基化参与了多种 代谢过程，例如细菌趋化性，精子迁移率，释放 神经递质，可能是某些酶活性。 Adomet也是 大量小分子的甲基供体（例如，生物合成 和/或各种Catechoiamine神经递质的代谢）。 我们研究了涉及的酶的结构和功能 甲基循环反应。相对较大的构象变化是 在底物结合或离开的结合后，在酶结构中观察到 来自活动地点的产品。在此赠款期间，takusagawa博士将 表征动态结构以及催化机制 按照X射线衍射方法遵循酶。 来自人类，大鼠，甲虫Jannaschii和 大肠杆菌。 来自大鼠的糖素N-甲基转移酶和鸟肽乙酸酯甲基转移酶 肝。大鼠肝脏和藻素粪便中的S-腺苷半胱氨酸水解酶。 来自大肠杆菌的S-腺苷甲硫代脱羧酶。 N10-甲基四氢叶酸合成酶 从圆柱梭菌。大鼠肝脏的丝氨酸脱水酶。 为了长期目标，我们想设计特定的抑制剂 这些酶是为了开发化学治疗剂的 获得的活性位点几何形状和所获得的酶的催化机制 在这个项目中。