Synthetic Nonheme Iron O2 Activation and S-Oxygenation

项目总结 这项建议的重点是单核非血红素铁络合物和酶，激活氧气和 含氧底物。一类重要的非血红素铁酶是硫醇双加氧酶，它利用一种 单铁中心和O2将硫醇底物氧化成亚磺酸。哺乳动物半胱氨酸双加氧酶 细菌3-巯基丙酸双加氧酶(P3MDO)是这类酶中的两种酶。的正常运作 CDO对于维持适当的半胱氨酸水平和生产半胱氨酸亚磺酸非常重要 哺乳动物体内半胱氨酸代谢的研究。CDO功能的丧失与许多疾病有关，包括 帕金森氏症和阿尔茨海默氏症，以及某些类型的癌症。这些物质的作用机制 人们对酶知之甚少。该提案中描述的努力包括设计和合成一个新的系列 激活O2并执行选择性底物氧化反应的铁络合物，包括S氧化， 类似于CDO和p3MDO。这项工作也与更大类别的非血红素铁氧合酶有关。这个 围绕金属离子的模块化有机配体支架将进行合理调整，以检测结构/功能 两性关系。对这些复合体的研究将提供基础知识，有助于描述 酶机理和设计选择性仿生铁氧化催化剂。新陈代谢产物的氧活性 含硫配体的非血红素铁络合物将通过设计捕集和/或 表征不稳定的Fe/O2衍生物种。这些方法包括使用低温诱捕 氧活化过程中的不稳定物种，以及停流紫外可见光谱等光谱方法 快速冷冻-猝灭捕获、共振拉曼、EPR、低温ESIMS和穆斯堡尔。密度 泛函理论(DFT)计算将支持和指导光谱和机理研究。一把钥匙 拟议工作的方面还包括对CDO和p3MDO酶的选择、平行研究。新的 氧中间体将成为目标，包括一种有希望的氧气衍生瞬变物种的特征 已经观察到有CDO。合成的络合物和酶的一氧化氮化学(NO)将是 经过研究，因为NO是众所周知的O2的信息量很大的替代品。分子的自旋态和电子结构 将确定新的FeNO物种，并将评估CDO中的第二和第三球相互作用。这个 所获得的基础知识应能为我们理解这些机制提供重大进展。 属于一大类非血红素铁氧合酶/氧化物酶。

PROJECT SUMMARY This proposal focuses on mononuclear nonheme iron complexes and enzymes that activate dioxygen and oxygenate substrates. An important class of nonheme iron enzymes is the thiol dioxygenases, which utilize a single iron center and O2 to oxidize thiol substrates to sulfinic acids. Mammalian cysteine dioxygenase (CDO) and bacterial 3-mercaptopropionate dioxygenase (p3MDO) are two enzymes in this class. Proper functioning of CDO is important for maintaining the appropriate levels of cysteine and producing cysteine sulfinic acid as part of cysteine metabolism in mammals. Loss of CDO function has been linked to a number of diseases including Parkinson's and Alzheimer's disease, as well as certain types of cancer. The mechanism of action of these enzymes is poorly understood. Efforts described in this proposal include the design and synthesis of a new series of iron complexes that activate O2 and carry out selective substrate oxidation reactions including S-oxygenation, similar to CDO and p3MDO. This work is also relevant to the larger class of nonheme iron oxygenases. The modular organic ligand scaffold surrounding the metal ion will be rationally adjusted to examine structure/function relationships. The study of these complexes will provide fundamental knowledge that will contribute to delineating enzyme mechanisms and to designing selective biomimetic iron oxidation catalysts. The O2 reactivity of new nonheme iron complexes bearing sulfur ligands will be examined by methods designed to trap and/or characterize unstable Fe/O2-derived species. These methods include the use of low temperatures to trap unstable species during O2 activation, and spectroscopic methods such as stopped-flow UV-vis coupled with rapid-freeze-quench trapping, resonance Raman, EPR, low-temperature ESIMS, and Mössbauer. Density functional theory (DFT) calculations will support and guide the spectroscopic and mechanistic studies. A key aspect of the proposed work also includes select, parallel studies on the enzymes CDO and p3MDO. New oxygen intermediates will be targeted, including the characterization of a promising O2-derived transient species already observed for CDO. The nitric oxide chemistry (NO) of both synthetic complexes and enzymes will be studied, as NO is a well-known and informative surrogate for O2. The spin states and electronic structures of the new FeNO species will be determined, and second and third sphere interactions in CDO will be assessed. The fundamental knowledge to be obtained should provide major advances in our understanding of the mechanisms of a large class of nonheme iron oxygenases/oxidases.