Synthetic Nonheme Iron O2 Activation and S-Oxygenation

项目摘要 这项建议的重点是单核非血红素铁复合物和酶，激活双氧， 基质。一类重要的非血红素铁酶是巯基双加氧酶，其利用一种 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 和细菌3-巯基丙酸双加氧酶（p3MDO）是这类酶中的两种。正常运作 CDO对于维持半胱氨酸的适当水平和产生半胱氨酸亚磺酸作为半胱氨酸的一部分是重要的。 半胱氨酸的代谢。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。这些的作用机制 对酶的了解很少。本提案所述的努力包括设计和综合一个新的系列， 铁络合物活化O2并进行选择性底物氧化反应，包括S-氧化， 类似于CDO和p3MDO。这项工作也是相关的更大类的非血红素铁加氧酶。的 围绕金属离子的模块化有机配体支架将被合理调整以检查结构/功能 关系。对这些复合体的研究将提供基础知识， 酶的作用机理和设计选择性仿生铁氧化催化剂。新的O2反应性 带有硫配体的非血红素铁络合物将通过设计用于捕获和/或 表征不稳定的Fe/O2衍生物种。这些方法包括使用低温来捕获 O2活化过程中的不稳定物种，以及光谱方法，如停流UV-vis结合 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。一个关键 所提出的工作的一个方面还包括对酶CDO和p3MDO的选择性平行研究。新 氧中间体将成为目标，包括一个有前途的O2衍生瞬态物种的表征 目前已在CDO合成复合物和酶的一氧化氮化学（NO）将被 研究，因为NO是一个众所周知的和翔实的替代O2。的自旋态和电子结构 新的FeNO物种将被确定，CDO中的第二和第三球相互作用将被评估。的 所获得的基础知识应能使我们对这些机制的理解取得重大进展 一个大类的非血红素铁加氧酶/氧化酶。

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.