Simulation of Proton and Hydride Transfer in Enzymes

酶中质子和氢化物转移的模拟

基本信息

批准号：
7385038
负责人：
SHARON HAMMES-SCHIFFER
金额：
$ 25.07万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7385038
关键词：
Active Sites Address Alanine Amino Acids Anabolism Aspartate Asthma Atherosclerosis Catalysis Chemotherapy-Oncologic Procedure Class Computing Methodologies Cysteine Data Dependence Deuterium Development Dihydrofolate Reductase Dihydroorotate dehydrogenase Disease Electron Transport Electronics Electrostatics Enzymes Eukaryota Eukaryotic Cell Folic Acid Antagonists Growth Health Human Hydrogen Hydrogen Bonding Immunity Immunosuppression Inflammation Isomerase Isomerism Isotopes Ketosteroids Kinetics Lead Leukotriene Production Lipoxins Lipoxygenase Maintenance Malaria Malignant Neoplasms Mammals Measurement Measures Motion Mutagenesis Mutation Nuclear Oxidation-Reduction Pharmaceutical Preparations Precursor RNA Prokaryotic Cells Property Proteins Protons Psoriasis Public Health Purines Purpose Pyrimidine Pyrimidine Nucleotides Pyrimidines Rabies Range Rate Reaction Research Research Personnel Rheumatoid Arthritis Role Series Serine Steroid Isomerases Steroid delta-isomerase Steroids Structure System Temperature Testing Tetrahydrofolates Tyrosine Unsaturated Fatty Acids X-Ray Crystallography base deprotonation enzyme deficiency folic acid metabolism inhibitor/antagonist mutant oxidation programs purine quantum research study response simulation single-molecule FRET steroid hormone

项目摘要

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 computational methods that include electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The calculations will probe the roles of electrostatics, hydrogen bonding, hydrogen tunneling, and protein motion in enzyme reactions. The four enzyme reactions that will be studied have been chosen on the basis of their biomedical importance and the availability of relevant experimental data. The first specific aim centers on the enzyme dihydrofolate reductase (DHFR), which is required for normal folate metabolism in prokaryotes and eukaryotes. This enzyme maintains 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 second 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 DMA synthesis. DHOD is medically relevant in that the immunosuppressive effects of inhibiting this enzyme have been used therapeutically to treat diseases such as rheumatoid arthritis. The third specific aim centers on the enzyme lipoxygenase. This enzyme aids in the production of leukotrienes and lipoxins, which regulate responses in inflammation and immunity. In mammals, lipoxygenases are medically relevant in that inhibitors have been used as drug agents to treat diseases such as asthma, atherosclerosis, psoriasis, and cancer. The fourth specific aim centers on the enzyme ketosteroid isomerase (KSI), which catalyzes the isomerization of steroids. In mammals, this enzyme is medically relevant in that it controls the synthesis of steroid hormones. Deficiencies of KSI and related enzymes in humans lead to a wide range of diseases and health problems. All of these studies are relevant to public health because the elucidation of the mechanisms will facilitate the development of more effective drugs for a broad range of diseases, including cancer, asthma, malaria, and rheumatoid arthritis.

描述（由申请人提供）：本研究的广泛，长期目标是阐明酶催化中氢转移的基本原理和机制，并解决生物学上重要的系统中未解决的问题。这些目标将通过包括电子和核量子效应的计算方法以及整个溶剂化酶的运动来实现。计算将探测静电，氢键，氢隧穿和蛋白质运动在酶反应中的作用。将根据其生物医学重要性和相关实验数据的可用性选择了将研究的四种酶反应。第一个特定的目的集中于二氢叶酸还原酶（DHFR），这是原核生物和真核生物中正常叶酸代谢所必需的。该酶维持支持嘌呤，嘧啶和氨基酸的生物合成所需的四氢叶酸水平。 DHFR在医学上是相关的，因为抑制DHFR用有效的抗凝胶抑制已成功地用于癌症化学疗法中。第二个特定目的集中于二氢易能酸酯脱氢酶（DHOD）。这种酶催化了嘧啶的生物合成中唯一的氧化还原反应，这是RNA和DMA合成的前体所必需的。 DHOD在医学上是相关的，因为抑制该酶的免疫抑制作用已在治疗上用于治疗类风湿关节炎等疾病。第三个特定目标集中于脂氧酶。这种酶有助于白细胞和脂毒素的产生，这些酶调节炎症和免疫的反应。在哺乳动物中，脂氧酶在医学上是相关的，因为抑制剂已被用作药物治疗哮喘，动脉粥样硬化，牛皮癣和癌症等疾病。第四个特定目标集中于酮酮异构酶（KSI），该酶催化类固醇的异构化。在哺乳动物中，该酶在医学上相关，因为它控制了类固醇激素的合成。人类中KSI和相关酶的缺陷导致广泛的疾病和健康问题。所有这些研究都与公共卫生有关，因为阐明该机制将有助于开发更有效的药物，包括癌症，哮喘，疟疾和类风湿关节炎。