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.

许多酶会催化生物学中的化学反应 系统。 其中一些酶位于〜瓶颈〜 生物途径的位置。 因此，对这些关键酶的研究 相关领域很重要。 S-介导的甲基化反应 腺苷硫氨酸（ADOMET）越来越被认为是 各种细胞调节中的重要控制因素 功能。 已知核酸的甲基化具有调节性 对DNA复制和转录以及RNA翻译的影响。 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， 释放神经传递，可能是某些酶活性。 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 反应是化学治疗设计的有吸引力的目标 代理商。 这是确定酶的晶体结构的建议 甲基循环。 具体而言，我们将确定 在此赠款期内遵循酶：1）人类S- Sdenosylmethionine合成酶，催化形成 来自ATP和蛋氨酸的ADOMET。 2）圭尼二乙酸 甲基转移酶催化依赖阿二的甲基化的甲基转移酶 鸟尼二乙酸形成肌酸。 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 活性位点的几何形状和酶的催化机制 在这个项目中获得了。