Molybdenum Pterin-Dithiolene Complexes for Model Studies of the Catalytic Site of

描述(申请人提供)：钼与健康的关系远不如铁、铜和锌那样为公众所熟知。然而，罕见的遗传性疾病导致钼酶受损，在最好的情况下会导致普遍的神经问题，在最坏的情况下会致命。不仅是人类，地球上几乎每个生物都依赖一种或多种钼或钨的酶。在所有复杂程度的生命中，钼酶都扮演着如此关键的角色，它们是碳、氮和硫元素的全球生物地球化学循环的关键参与者。尽管研究界在了解钼和钨酶方面取得了巨大的进展，但对钼酶和钨酶共同的特殊配体的作用了解很少。这种配体，绰号钼多蝶呤，是一种蝶呤取代的二硫杂菲螯合物，在所有生物化学中都是独一无二的。虽然人们已经了解了许多关于为什么二硫烯络合物适合于这些酶的金属催化的电子转移反应，但对蝶呤取代基的需求在很大程度上仍然是一个谜。作为本项目重点的新模型包含了一个附加了蝶呤的二硫茂络合物，这两个关键特征都是钼和钨酶中钼多蝶呤的关键特征，因此它们对于研究蝶呤取代的与钼配位的二硫杂菲配体的蝶呤氧化还原化学域的潜力将是独一无二的。拟议的项目寻求详细了解蝶呤-二硫烯结构的独特方面，这些独特方面既影响钼上的反应活性，也影响配位的蝶呤-二硫烯配体本身的反应活性。具体目标是：(A)通过化学和电化学方法探索与钼配位的蝶呤-二硫杂环戊烯的氧化还原行为；(B)研究不同还原程度的蝶呤类化合物对钼-二硫杂环戊烯单元的电子效应；(C)完成所有模型化合物的全谱和结构表征；(D)开始研究二硫杂环戊烯在钼和铜之间的转移。这项拟议工作的结果需要进一步了解钼酶在人类代谢过程中的功能，甚至可能是功能障碍。预计对这些电子结构与钼活性中心非常相似的模型的研究将：a)揭示所有钼蝶呤酶活性中心的蝶呤的特殊用途；b)提供光谱和结构基准，以帮助解释酶的类似结果；c)提供理解钼和钨酶活性中心化学所需的基础化学示例，可能为未来的治疗奠定基础。钼与健康的关系远不如常见的必需金属铁、铜和锌那么为公众所熟知，然而，罕见的遗传性疾病导致钼酶受损，往好了说会导致普遍的神经问题，往坏了说是致命的。最近，人们发现了铜水平和钼酶之间可能存在的联系。这个项目的目标是更详细地了解钼酶中钼的独特配体环境是如何对酶活性起关键作用的。

DESCRIPTION (provided by applicant): The relationship of molybdenum to health is far less well known by the general public than that of familiar essential metals iron, copper and zinc. Yet rare inherited diseases resulting in compromised molybdenum enzymes lead to pervasive neurological problems at best and are fatal at worst. Not only humans, but nearly every organism on this planet relies on one or more molybdenum or tungsten enzymes. Having such key roles for life at all levels of complexity, molybdenum enzymes are key participants in the global biogeochemical cycling of the elements carbon, nitrogen and sulfur. Despite huge progress made by the research community in understanding molybdenum and tungsten enzymes, very little is understood about the role of the special ligand common to both Mo and W enzymes. This ligand, nicknamed molybdopterin, is a pterin-substituted dithiolene chelate and is unique in all of biochemistry. While much has been learned about why a dithiolene chelate is suited for the electron transfer reactions catalyzed by the metals of these enzymes, the requirement of the pterin substituent remains largely a mystery. The new models that are the focus of this project incorporate a dithiolene chelate appended by a pterin, both of the key features of molybdopterin in all Mo and W enzymes, and therefore will be unique for their potential to study the gamut of pterin redox chemistry for a pterin-substituted dithiolene ligand coordinated to Mo. The proposed project seeks a detailed understanding of the unique aspects of the pterin-dithiolene structure that influence both the reactivity at molybdenum and within the coordinated pterin-dithiolene ligand itself. Specific objectives are: (a) explore the redox behavior of a molybdenum-coordinated pterin-dithiolene by chemical and electrochemical methods; (b) to probe the electronic effects of pterins at different levels of reduction on the Mo-dithiolene unit; (c) to accomplish full spectroscopic and structural characterization of all model compounds; (d) to begin an investigation of dithiolene transfer between molybdenum and copper. The results of the proposed work are needed to make further progress in understanding the function, and possibly the dysfunction, of the molybdenum enzymes in human metabolic processes. It is expected that studies of these models whose electronic structure closely resembles that of the molybdenum active site will: a) reveal the special purpose of the pterin in the active site of all molybdopterin enzymes; b) provide spectroscopic and structural benchmarks to aid interpretation of analogous results from the enzymes and c) provide examples of fundamental chemistry needed to understanding the active site chemistry of Mo and W enzymes, possibly laying groundwork for future therapies. The relationship of molybdenum to health is far less well known by the general public than that of familiar essential metals iron, copper and zinc, yet rare inherited diseases resulting in compromised molybdenum enzymes lead to pervasive neurological problems at best and are fatal at worst. More recently, a possible link between copper levels and molybdenum enzymes has been discovered. The goal of this project is to gain a more detailed understanding of how the unique ligand environment of molybdenum in molybdoenzymes is critical to the enzyme activity.