STRUCTURAL STUDIES OF METHYL CYCLE ENZYMES

甲基环酶的结构研究

• 批准号: 6385652
• 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/6385652
• 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.

由S-腺苷甲硫氨酸（SNAMet）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。核酸的甲基化是 已知对DNA复制和转录具有调节作用， 翻译.蛋白质甲基化参与多种生物学活性的调节。 代谢过程，如细菌趋化性、精子活动性、 神经递质和可能的某些酶活性。同时， 大量小分子的甲基供体（例如，生物合成 和/或各种儿茶酚胺神经递质的代谢）。 我们已经研究了参与的酶的结构和功能， 甲基循环反应。一个相对较大的构象变化是 在与底物结合或离开时在酶结构中观察到 从活跃的网站。在此期间，Takusagawa博士将 表征其动态结构和催化机制 用X射线衍射法测定酶的活性。 来自人、大鼠、詹氏甲烷球菌和 E.杆菌 大鼠甘氨酸N-甲基转移酶和胍基乙酸甲基转移酶 肝脏来自大鼠肝脏和粪产碱菌的S-腺苷高半胱氨酸水解酶。 S-腺苷甲硫氨酸脱羧酶。杆菌N10-甲酰四氢叶酸合成酶 来自柱孢梭菌。来自大鼠肝脏的丝氨酸转氨酶。 为了长期的目标，我们想设计特定的抑制剂 为了开发化疗药物， 得到了酶的活性中心几何构型和催化机理 在这个项目中。