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尚未解决的问题。这些目标将通过包括电子和核量子效应以及整个溶剂化酶的运动的计算方法来实现。计算将探讨酶反应中静电、氢键、氢隧穿和蛋白质运动的作用。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。第一个具体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的正常叶酸代谢所需的。这种酶维持嘌呤、嘧啶和氨基酸生物合成所需的四氢叶酸水平。DHFR在医学上是相关的，因为用有效的抗叶酸剂抑制DHFR已成功地用于癌症化疗。第二个具体目标集中在酶二氢乳清酸脱氢酶（DHOD）。这种酶催化嘧啶生物合成中唯一的氧化还原反应，这是RNA和DMA合成所需的前体供应。DHOD在医学上是相关的，因为抑制这种酶的免疫抑制作用已经在治疗上用于治疗疾病，如类风湿性关节炎。第三个具体目标集中在酶脂氧合酶。这种酶有助于产生白三烯和脂氧素，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疾病如哮喘、动脉粥样硬化、牛皮癣和癌症的药物。第四个具体目标集中在酶酮甾体异构酶（KSI），它催化类固醇的异构化。在哺乳动物中，这种酶与医学有关，因为它控制类固醇激素的合成。人类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，因为阐明这些机制将有助于开发更有效的药物，用于治疗广泛的疾病，包括癌症，哮喘，疟疾和类风湿性关节炎。

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.