Synthesis and Spectroscopy of Ferric Superoxo Models for Non-Heme Enzyme Intermediates

 描述(申请人提供)：非血红素，含铁的加氧酶参与各种重要的生物医学过程，包括抗生素的生物合成(包括氯霉素和青霉素)，脱氧核糖核苷酸的生成(DNA的关键组成部分)，以及储存铁以防止破坏Fenton类型的化学(通过铁蛋白的亚铁氧基酶位置)。了解加氧酶如何利用活化的铁-氧物种进行这些转化是至关重要的。尽管有大量关于铁-氧和铁-过氧基物种的作用的研究，但已知的光谱可及的铁-超氧化合物很少。这是令人惊讶的，因为铁-超氧物种被认为是几乎所有非血红素含铁加氧酶催化循环的早期中间体。这项建议的目标是产生光谱易处理的Fe(III)-与非血红素含铁加氧酶相关的超氧物种。这将通过开发一种针对单核非血红素Fe(III)-超氧物种的合成方法来实现。我们假设，通过适当结合反应条件和配体设计特征(包括配体的碱性、空间位阻和氢键供体能力)，我们将能够生成第一个人工合成的单核非血红素Fe(III)-超氧物种。我们还将应用类似的设计原理来从含有Fe(II)中心的双核前驱体生成Fe(III)-超氧化合物。合成的Fe(III)-超氧化合物将通过多种光谱方法进行全面的表征，包括UV-Vis、XAS、共振拉曼光谱、EPR和穆斯堡尔光谱。这将使人们能够了解化合物的初级和次级配位球特征与铁-超氧物种的结构和电子特征之间的关系。到目前为止，还没有一种非血红素铁-超氧化合物通过拉曼光谱、EPR光谱和穆斯堡尔光谱的组合来完全表征，这是对该领域的理解的一个重大差距。事实上，只有一个这样的超氧化合物被共振拉曼表征，与其他已知的超氧化物化合物(1043-1207 cm-1)相比，1310 cm-1的O-O伸缩频率是异常高的。还将探索合成的Fe(III)-超氧化合物的反应性，以便建立与电子和结构参数的反应性关系。总体而言，这项研究对理解超氧化物中间体在非血红素含铁加氧酶领域中的作用具有潜在的变革性。

 DESCRIPTION (provided by applicant): Non-heme, iron-containing oxygenases are involved in various biomedically important processes, including the biosynthesis of antibiotics (including chlorobiocin and penicillin), the generation of deoxyribonucleotides (key building blocks of DNA), and the storage of iron to prevent damaging Fenton-type chemistry (via the ferroxidase site of ferritin). Understanding how oxygenases use activated iron-oxygen species to carry out these transformations is of paramount importance. Despite the wealth of studies on the role of iron-oxo and iron-peroxo species, there is a paucity of spectroscopically accessible iron-superoxo compounds known. This is surprising given that iron-superoxo species are proposed as early intermediates in the catalytic cycles of almost every non-heme iron-containing oxygenase enzyme. The goal of this proposal is to generate spectroscopically tractable Fe(III)-superoxo species of relevance to non-heme iron-containing oxygenases. This will be accomplished by developing a synthetic methodology for mononuclear non-heme Fe(III)-superoxo species. We hypothesize that by appropriate combination of reaction conditions and ligand design features (including ligand basicity, steric bulk and hydrogen bond donor ability) we will be able to generate the first synthetic mononuclear non-heme Fe(III)-superoxo species. We will also apply similar design principles to the generation of Fe(III)-superoxo compounds from dinuclear precursors containing a Fe(II) center. The synthetic Fe(III)-superoxo compounds will be comprehensively characterized by a variety of spectroscopic methods including UV-vis, XAS, resonance Raman, EPR, and Mössbauer spectroscopy. This will allow the establishment of an understanding of the relationship between primary- and secondary- coordination sphere features of the compounds to the structural and electronic features of iron-superoxo species. To date no non-heme iron-superoxo compound has been fully characterized by a combination of Raman, EPR and Mössbauer spectroscopy, and this is a significant gap in understanding for the field. In fact, only a single such superoxo compound has been characterized by resonance Raman, and the O-O stretching frequency of 1310 cm-1 is anomalously high compared to other known superoxide compounds (1043-1207 cm-1). The reactivity of the synthesized Fe(III)-superoxo compounds will also be explored in order to establish a reactivity relationship to electronic and structural parameters. Overall, this research has the potential to be transformative to understanding the role of superoxide intermediates in the field of non-heme iron-containing oxygenases.