Simulation of Protein and Hydride Transfer in Enzymes

酶中蛋白质和氢化物转移的模拟

• 批准号: 6579729
• 负责人: SHARON HAMMES-SCHIFFER
• 金额: $ 23.05万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579729
• 关键词: alcohol dehydrogenase; catalyst; chemical transfer reaction; computer simulation; dihydrofolate reductase; enzyme mechanism; enzyme structure; glucose oxidase; hydrogen ions; lipoxygenase; mathematical model; molecular dynamics; oxidation reduction reaction; oxidoreductase; quantum chemistry

DESCRIPTION (provided by applicant): The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms of hydrogen transfer in enzyme catalysis and to address unresolved issues in biologically important systems. These objectives will be accomplished with a recently developed mixed quantum-classical molecular dynamics approach that includes electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The first specific aim is to determine the impact of enzyme structure and motion on catalysis. The second specific aim is to clarify the role of nuclear quantum effects such as zero point motion and hydrogen tunneling in enzyme catalysis. The remaining three specific aims address these issues for three enzyme reactions, which have been chosen on the basis of their biomedical importance and the availability of relevant experimental data. The third specific aim centers on the enzyme dihydrofolate reductase (DHFR), which is required for normal folate metabolism in prokaryotes and eukaryotes. This enzyme is essential for the maintenance of tetrahydrofolate levels required to support the biosynthesis of purines, pyrimidines, and amino acids. DHFR is medically relevant, in that inhibition of DHFR with potent antifolates has been used successfully in cancer chemotherapy. The fourth specific aim centers on the enzyme dihydroorotate dehydrogenase (DHOD). This enzyme catalyzes the only redox reaction in the biosynthesis of pyrimidines, which are required for the supply of precursors for RNA and DNA synthesis. DHOD is medically relevant, in that the immunosuppressive effects of inhibiting this enzyme have been used therapeutically. The fifth specific aim centers on lipoxygenase, which serves numerous vital roles in plants and mammals. In mammals, lipoxygenases are medically relevant, in that they mediate processes such as asthma, atherosclerosis, psoriasis, inflammatory diseases, and cancer growth.

描述(申请人提供)：这项研究的长期目标是阐明酶催化中氢转移的基本原理和机制，并解决生物重要系统中尚未解决的问题。这些目标将通过最近开发的混合量子-经典分子动力学方法来实现，该方法包括电子和核量子效应，以及整个溶剂化酶的运动。第一个具体目标是确定酶的结构和运动对催化的影响。第二个具体目标是阐明核量子效应，如零点运动和氢隧道效应在酶催化中的作用。剩下的三个具体目标针对三个酶反应的这些问题，这三个反应是根据它们的生物医学重要性和相关实验数据的可用性而选择的。第三个特定目标是二氢叶酸还原酶(DHFR)，它是原核生物和真核生物叶酸正常代谢所必需的。这种酶对维持四氢叶酸水平是必不可少的，这是支持嘌呤、嘧啶和氨基酸的生物合成所必需的。DHFR在医学上是相关的，因为用有效的抗叶酸抑制DHFR已成功地用于癌症化疗。第四个具体目标是二氢罗酸脱氢酶(DHOD)。该酶催化生物合成嘧啶类化合物中唯一的氧化还原反应，这是为RNA和DNA合成提供前体所必需的。DHOD在医学上是相关的，因为抑制这种酶的免疫抑制作用已经被用于治疗。第五个特定的目标是脂氧合酶，它在植物和哺乳动物中扮演着许多重要的角色。在哺乳动物中，脂氧合酶在医学上是相关的，因为它们介导了哮喘、动脉粥样硬化、牛皮癣、炎症性疾病和癌症生长等过程。