Investigation of a Pterin-Dithiolene Model Complex for the Molybdenum Cofactor

总结/摘要 钼（Mo）对地球上几乎所有生物的健康至关重要。人类有绝对的 需要几种钼酶，特别是一个是关键的适当胚胎 发展到成熟。人类遗传性疾病导致钼酶受损 最好的情况下会导致普遍的神经问题，最坏的情况下会导致婴儿死亡。尽管经过了五十年的研究 对钼酶的功能和某些结构方面的独特的配体螯合钼， 这些蛋白质仍然是一个谜。该配体是蝶呤取代的二硫杂环戊烯螯合物，并且仅存在于 钼和相关的钨酶。辅酶引起的人类疾病 功能障碍与蝶呤-二硫杂环戊烯生物合成途径中的错误有关， 配体在酶功能中的关键作用。 该项目将对Mo-吡喃蝶呤的化学行为和反应性进行详细研究， 二硫杂环戊烯模型复合物被设计为与酶中的Mo位点几乎相同。目标是 了解构象和氧化还原在蝶呤的变化如何影响整个电子结构 蝶呤-二硫纶配体在酶中与Mo配位。特别令人感兴趣的是， 环对断裂的反应性，以及当蝶呤被氧化时，已知蝶呤氧化还原化学的范围如何改变。 稠合到吡喃环和二硫杂环戊烯配体上。具体目标是：（a）确定 对螯合到Mo上蝶呤-二硫杂环戊烯配体的吡喃环化和裂解的影响;（B）理解 用化学和电化学方法研究吡喃蝶呤二硫纶配体的氧化还原化学和性质 方法;（c）探测不同还原水平的蝶呤对Mo-二硫纶的电子效应 单位;和（d）完成所有模型化合物的完整光谱和结构表征。的 这些结果对于完全理解Mo位点的功能以及蝶呤-二硫杂环戊烯 可能与功能失调的酶有关预计这些研究将：a）揭示什么化学物质 在Mo酶内存在对蝶呤-二硫杂环戊烯配体的反应性，并且这种理解将提供B） 蛋白质环境如何影响蝶呤行为的见解;（c）提供光谱和 结构基准，以帮助解释来自酶的类似结果，以及（d）描述基本的 Mo和W酶的活性位点化学的化学性质被开发用于可能的未来疗法。

Summary/Abstract Molybdenum (Mo) is critical to the health of nearly every organism on earth. Humans have an absolute requirement for several molybdenum enzymes and one in particular is critical for proper embryo development to maturity. Inherited diseases in humans result in compromised molybdenum enzymes causing pervasive neurological problems at best and infant fatalities at worst. Despite fifty years' of research on molybdenum enzymes, the function and certain structural aspects of the unique ligand chelating Mo in these proteins remain a mystery. This ligand is a pterin-substituted dithiolene chelate and is found only in molybdenum and the related tungsten enzymes. Human diseases resulting from molybdoenzyme disfunction have been linked to errors in the pterin-dithiolene biosynthetic path which underscores the pivotal role of the ligand in enzyme function. This project will undertake a detailed study of the chemical behavior and reactivity of a Mo-pyranopterin- dithiolene model complex designed to be nearly identical to the Mo site in the enzymes. The goal is to understand how conformation and redox changes at the pterin influence the electronic structure of the entire pterin-dithiolene ligand coordinated to Mo in the enzymes. Of particular interest is establishing the pyran ring reactivity towards scission and how the gamut of known pterin redox chemistry is altered when pterin is fused to a pyran ring and a dithiolene ligand. Specific objectives are: (a) to determine those factors that influence pyran ring cyclization and cleavage on pterin-dithiolene ligands chelated to Mo; (b) to understand the redox chemistry and properties of pyranopterin dithiolene ligands using chemical and electrochemical methods; (c) to probe the electronic effects of pterins at different levels of reduction on the Mo-dithiolene unit; and (d) to accomplish full spectroscopic and structural characterization of all model compounds. The results are critical to a complete understanding of how the Mo site functions and how the pterin-dithiolene might be involved in dysfunctional enzymes. It is expected that these studies will: a) reveal what chemical reactivity exists for pterin-dithiolene ligands within the Mo enzymes, and this understanding will b) provide insights for how the protein environment could influence pterin behavior; (c) provide spectroscopic and structural benchmarks to aid interpretation of similar results from the enzymes and (d) describe fundamental chemistry of the active site chemistry of Mo and W enzymes to be exploited for possible future therapies.