Spectroscopic Studies of Molybdoenzymes and Models

描述（由申请方提供）：拟议研究的广泛、长期目标是了解几何结构和电子结构对吡喃蝶呤钼酶功能的贡献，特别是与了解黄嘌呤氧化酶、醛氧化酶和亚硫酸盐氧化酶的活性机制相关，因为这些是在人体中发现的关键酶。拟议研究计划的具体目标是：1）全面了解黄嘌呤氧化酶（XO）中的还原半反应，2）使用XO相关一氧化碳脱氢酶（CODH）活性位点的小分子类似物来了解电子结构对催化的贡献，3）关联电子和几何结构对亚硫酸盐氧化酶（SO）中氧原子和电子转移反应性的贡献，和4）确定DMSO还原酶位点对称性如何有助于酶催化。患有钼辅因子缺乏症的个体表现出严重的神经系统症状和早期儿童死亡。XO的生理功能似乎是相当复杂的，并且通过以下事实来例证：XO最近被认为在先天性免疫系统的功能中以及在缺血后再灌注损伤中发挥核心作用。AO和XO最近都涉及前体药物活化，药物代谢，并在特定条件下，NO合酶活性。与XO相比，关于AO的全部病理生理学相关性知之甚少。然而，AO催化磺胺类药物的还原、抗癌前药的活化，并且最近已显示将泛昔洛韦代谢为有效的抗病毒药物泛昔洛韦，已发现泛昔洛韦对诸如单纯疱疹、水痘带状疱疹、爱泼斯坦-巴尔和B肝炎的病毒感染有效。在脊椎动物中，SO存在于线粒体中！亚硫酸盐的生理重要氧化代表半胱氨酸和甲硫氨酸氧化降解的最终步骤。该研究计划将利用结合光谱方法，辅以计算研究，对模型和酶进行详细的电子结构描述，以及这种电子结构如何有助于其活性机制。钼酶对人类健康至关重要。我们对它们在药物代谢、自由基损伤和免疫系统中的作用的新认识强调了它们在各种健康相关问题中的作用。

DESCRIPTION (provided by applicant): The broad, long-term objectives of the proposed research are to understand geometric and electronic structure contributions to the function of pyranopterin molybdenum enzymes, with particular relevance to understanding the mechanism of activity in xanthine oxidase, aldehyde oxidase and sulfite oxidase as these are key enzymes found in humans. The specific aims of the proposed research plan are to 1) develop a comprehensive understanding of the reductive half-reaction in xanthine oxidase (XO), 2) use small molecule analogues of the XO related carbon monoxide dehydrogenase (CODH) active site to understand electronic structure contributions to catalysis, 3) correlate electronic and geometric structure contributions to oxygen atom and electron transfer reactivity in sulfite oxidase (SO), and 4) determine how the DMSO reductase site symmetry contributes to enzymatic catalysis. Individuals suffering from molybdenum cofactor deficiency display severe neurological symptoms and early childhood death. The physiological function of XO appears to be quite complex, and is exemplified by the fact that XO has recently been suggested to play a central role in the function of the innate immune system, and in postischemic reperfusion injury. Both AO and XO have recently been implicated in pro-drug activation, drug metabolism and, under specific conditions, NO synthase activity. Compared to XO, very little is known concerning the full pathophysiological relevance of AO. However, AO catalyzes the reduction of sulfa drugs, the activation of anticancer prodrugs, and has recently been shown to metabolize famciclovir to the potent antiviral penciclovir, which has been found to be effective against such viral infections as herpes simplex, varicella zoster, Epstein-Barr, and hepatitis B. In vertebrates, SO is found in the mitochondria! intermembrane space where the physiologically important oxidation of sulfite represents the terminal step in the oxidative degradation of cysteine and methionine. The research plan will utilize a combined spectroscopic approach, complimented by computational studies, on both models and enzymes to develop a detailed electronic structure description of the active site and how this electronic structure contributes to their mechanism of activity. Molybdenum enzymes are of key importance to human health. Our emerging understanding of their role in drug metabolism, free-radical damage, and the immune system underscore their role in a variety of health related issues.