Simulation of Proton and Hydride Transfer in Enzymes

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，并解决生物学重要系统中未解决的问题。这些目标将通过计算方法来实现，包括电子和核量子效应，以及整个溶剂化酶的运动。这些计算将探讨静电、氢键、氢隧穿和酶反应中的蛋白质运动的作用。将研究的四种酶反应是根据其生物医学重要性和相关实验数据的可用性选择的。第一个特定的目标集中在酶二氢叶酸还原酶（DHFR），这是在原核生物和真核生物正常叶酸代谢所必需的。这种酶维持四氢叶酸水平，以支持嘌呤、嘧啶和氨基酸的生物合成。DHFR在医学上是相关的，用有效的抗叶酸盐抑制DHFR已成功地用于癌症化疗。第二个具体目标集中在酶二氢酸脱氢酶（DHOD）。这种酶在嘧啶的生物合成中催化唯一的氧化还原反应，这是RNA和DMA合成所需的前体的供应。DHOD在医学上是相关的，因为抑制这种酶的免疫抑制作用已被用于治疗类风湿性关节炎等疾病。第三个具体目标集中在脂氧合酶上。这种酶有助于白三烯和脂毒素的产生，它们调节炎症和免疫反应。在哺乳动物中，脂氧合酶在医学上是相关的，因为抑制剂已被用作治疗哮喘、动脉粥样硬化、牛皮癣和癌症等疾病的药物。第四个具体目标集中在酶酮类固醇异构酶（KSI），它催化类固醇异构化。在哺乳动物中，这种酶在医学上是相关的，因为它控制类固醇激素的合成。人类缺乏KSI和相关酶会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，因为阐明这些机制将有助于开发更有效的药物，治疗包括癌症、哮喘、疟疾和类风湿性关节炎在内的广泛疾病。

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.