STRUCTURAL STUDIES OF METHYL CYCLE ENZYMES

许多酶催化生物化学反应 系统. 其中一些酶位于~瓶颈~ 生物学路径的位置。 因此，对这些关键酶的研究 和相关领域是重要的。 S-甲基化反应 腺苷甲硫氨酸（adenosylmethionine，ADMet）越来越被认为是 重要的控制因素，在调节各种细胞 功能协调发展的 已知核酸的甲基化具有调控性。 对DNA复制和转录以及RNA翻译的影响。 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， 释放神经传递和可能的某些酶活性。 蛋氨酸也是大量小分子的甲基供体 (e.g.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 反应是设计化疗药物的有吸引力的靶点， 剂. 这是一个建议，以确定晶体结构的酶， 甲基循环。 具体来说，我们将确定的结构， 以下酶在本授权期：1）人类S- 腺苷甲硫氨酸合成酶，其催化 从ATP和蛋氨酸中除去蛋氨酸。 2)胍基乙酸盐 甲基转移酶，其催化二甲双胍依赖性甲基化 形成肌酸。 为了长期的目标，我们想设计特定的抑制剂 这些酶，以开发化学治疗剂，使用 活性中心的几何形状和酶的催化机制 在这个项目中获得。

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.