Non-heme Fe(IV)-oxo Intermediates: Structure and Reactivity

非血红素 Fe(IV)-oxo 中间体：结构和反应性

• 批准号: 0642058
• 负责人: Carsten Krebs
• 金额: $ 59.5万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0642058&HistoricalAwards=false
• 关键词: Non; heme; Fe; IV; oxo

This award, co-funded by the Biomolecular Systems Cluster in the Division of Molecular and Cellular Biosciences and the Inorganic, Bioinorganic and Organometallic Chemistry program in the Division of Chemistry supports research by Professors Carsten Krebs and Joseph Bollinger at the Pennsylvania State University to study Fe(IV)-oxo intermediates involved in the activity of prolyl-4-hydroxylase (P4H).The biosyntheses of many organic molecules require selective oxidation reactions. Of particular importance is the oxidation of aliphatic C-H bonds. This reaction is particularly challenging, because the inertness of the C-H bond requires extremely strong oxidants. Furthermore, most organic molecules contain multiple C-H bonds that could be targeted by the strong oxidant, thus potentially leading to reaction mixtures. In nature, these reactions are carried out at metalloenzyme active sites. The enzymes are capable of reacting with molecular oxygen to create highly reactive intermediates. These intermediates are sufficiently reactive to activate the inert C-H bond. Complexes containing iron in the +IV oxidation state coordinated by an oxo ligand, also known as the Fe(IV)-oxo or ferryl species, are arguably the most powerful, versatile, and environmentally friendly oxidants known. Detailed insight into the structure and reactivity of such intermediates can be obtained by a combination of kinetic and spectroscopic methods. The kinetic methods allow the intermediate to be trapped and provide information about how fast it forms and decays. Samples containing large amounts of the reactive species can then be analyzed by various spectroscopic methods, which provide detailed insight into their chemical nature. Several ferryl intermediates that do not contain the heme cofactor (a.k.a. non-heme ferryl complexes) have recently been reported and characterized in detail by the Bollinger/Krebs group. The enzymes under investigation catalyze the hydroxylation of aliphatic C-H bonds of their substrates. This work will now be extended to study several other non-heme-iron enzymes that catalyze distinct oxidation outcomes, including halogenation. It is expected that these studies will provide unprecedented insight into the mechanisms that these enzymes employ to oxidize organic substrates. In terms of the broader impact, a key feature of this work is that it is highly interdisciplinary, in line with the general trend in science in recent years. Facilitating the development of expertise in multiple, distantly related research areas is imperative for effectively training the next generation of scientists. This project is carried out at the interfaces of inorganic chemistry, biochemistry, molecular biology, and physical chemistry. In particular, it emphasizes concepts of enzyme kinetics, coordination chemistry, and spectroscopy. Thus, it will facilitate unique training in these areas. The co-PIs will organize a summer symposium on the subject of their research, characterization of reaction intermediates. As part of this symposium, there will be a workshop for students and researchers attending the symposium. During this workshop, participants will be trained in the experimental methods of this research area and the associated interpretation of data. The expectation is that students and researchers will be able to adapt these methods more easily to their own research.

This award, co-funded by the Biomolecular Systems Cluster in the Division of Molecular and Cellular Biosciences and the Inorganic, Bioinorganic and Organometallic Chemistry program in the Division of Chemistry supports research by Professors Carsten Krebs and Joseph Bollinger at the Pennsylvania State University to study Fe(IV)-oxo intermediates involved in the activity of prolyl-4-hydroxylase （P4H）。许多有机分子的生物合成需要选择性氧化反应。特别重要的是脂肪族C-H键的氧化。这种反应特别具有挑战性，因为C-H键的惰性需要极强的氧化剂。此外，大多数有机分子都包含多个C-H键，这些C-H键可能是由强氧化剂靶向的，因此可能导致反应混合物。在本质上，这些反应是在金属酶的活性位点进行的。这些酶能够与分子氧反应以产生高反应性中间体。这些中间体足够反应以激活惰性C-H键。 +IV氧化状态中包含铁的复合物，由氧化配体（也称为Fe（iv） - 氧或渡轮物种）是最强大，最通用且环保的氧化剂。可以通过动力学和光谱方法的组合获得对此类中间体的结构和反应性的详细见解。动力学方法使中间体被困并提供有关其形成和衰减速度的信息。然后可以通过各种光谱方法分析包含大量反应物种的样品，这些方法可提供对其化学性质的详细见解。 Bollinger/Krebs组详细介绍了几个不包含血红素辅因子（又称非血红素渡过配合物）的渡轮中间体。正在研究的酶催化其底物的脂肪族C-H键的羟基化。现在，这项工作将扩展到研究其他几种非血红素铁酶，以催化明显的氧化结果，包括卤素化。预计这些研究将为这些酶氧化有机底物的机制提供前所未有的见解。就更广泛的影响而言，这项工作的一个关键特征是它是高度跨学科的，这符合近年来科学的总体趋势。促进在多个，遥远的研究领域的专业知识的发展对于有效培训下一代科学家至关重要。该项目是在无机化学，生物化学，分子生物学和物理化学的界面上进行的。特别是，它强调了酶动力学，协调化学和光谱法的概念。因此，它将促进这些领域的独特培训。 CO-PIS将在其研究主题上组织夏季研讨会，表征反应中间体。作为本次研讨会的一部分，将为参加研讨会的学生和研究人员举办研讨会。在此研讨会期间，将对参与者进行该研究领域的实验方法和数据解释的培训。期望学生和研究人员能够更轻松地适应自己的研究。