STRUCTURAL STUDIES OF METHYL CYCLE ENZYMES

甲基环酶的结构研究

• 批准号: 2900633
• 负责人: Fusao None Takusagawa
• 金额: $ 12.4万
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900633
• 关键词: X ray crystallography; acetates; benzopyrenes; chemical models; computer simulation; enzyme structure; folate; glycine; homocysteine; methyl group; methyltransferase; peptidases; tetrahydrofolates

A number of enzyme catalyze the chemical reactions in biological systems. Some of these enzymes are located in the ~bottleneck~ positions of biological pathways. Thus, the study of these key enzymes and related areas is important. Methylation reactions mediated by S- adenosylmethionine (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 processess such as bacterial chemotaxis, sperm mobility, release of neurotransmission 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 catecholamine neurotransmitters). Thus, the enzymes that catalyze the methylation reactions are attractive targets for the design of chemotherapeutic agents. This is a proposal to determine the crystal structures of the enzyme in the methyl cycle. Specifically we will determine the structures of the following enzymes in this grant period: 1) Human S- sdenosylmethionine synthetase which catalyzes the formation of AdoMet from ATP and methionine. 2) Guanidinoacetate methyltransferase which catalyzes the AdoMet-dependent methylation of guanidinoacetate to form creatine. 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.

许多酶在生物体内催化化学反应。 系统。其中一些酶位于~瓶颈~~ 生物路径的位置。因此，对这些关键酶的研究 相关领域也很重要。S介导的甲基化反应- 腺苷蛋氨酸(ADOMet)正日益被公认为 调控多种细胞因子的重要控制因素 功能。众所周知，核酸的甲基化具有调节作用 对DNA复制和转录以及RNA翻译的影响。 蛋白质甲基化参与调节多种 代谢过程，如细菌趋化性，精子流动性， 释放神经传递和可能的某些酶活性。 ADOMet也是大量小分子的甲基供体 (例如，各种儿茶酚胺的生物合成和/或代谢 神经递质)。因此，催化甲基化的酶 反应是化疗药物设计的重要靶点 探员们。 这是一项确定该酶晶体结构的建议 甲基循环。具体来说，我们将确定 本授权期内的下列酵素：1)人类S- 硫代蛋氨酸合成酶，催化形成 来自三磷酸腺苷和蛋氨酸的ADOMet。2)乙酸胍 催化ADOMet依赖甲基化的甲基转移酶 生成肌酸。 为了长期目标，我们希望设计特定的抑制剂。 以开发使用这些酶的化疗药物 酶的活性中心几何构型及其催化机理 在这个项目中获得的收益。