Modeling the Active Site and Reactivity of Cyt. P450 Enzymes: A New Beginning

在这个由化学部化学结构，动力学机制B计划资助的项目中，密歇根大学化学系的Nicolai Lehnert教授将为细胞色素P450酶家族的活性位点开发新的模型系统。这些酶在人类中通过活化惰性C-H键对类固醇的生物合成和药物代谢起关键作用，因此在制药和化学工业中具有普遍意义。该项目的目标是建立模型系统，将蛋白质基质的第二配位球效应纳入合成模型系统。 然后，新的模型系统将用于（a）探索细胞色素P450活化O2和NO的分子机制，以及（B）开发细胞色素P450仿生催化剂用于工业应用，特别是用于燃料电池中的O2还原和有机分子的C-H键活化。 该项目位于无机，生物和有机化学的界面，因此非常适合各级科学家的教育。 这个研究小组也有能力为底特律地区代表性不足的少数民族高中生提供暑期研究实习机会。 由于细胞色素P450在实际应用中的巨大潜力，先前已经创建了许多模型系统来模拟细胞色素P450的血红素-硫醇盐活性位点。然而，这些仿生复合物中的大多数在O2或NO的存在下容易降解，即使在铁（静息）状态下也是如此。这种意想不到的稳定性缺乏是由于价态互变异构现象，其中这些络合物的硫醇铁基态在室温下与硫代亚铁态平衡。基于这些发现，该研究小组计划研究一系列新的血红素-硫醇盐模型复合物，其包含（a）氢键稳定的硫醇盐配体，和（B）不同类型的栅栏卟啉，其中第二配位球效应被纳入模型系统的远端口袋。这一系列新的复合物将用于系统地研究血红素硫醇盐活性位点与O2和NO的反应性，以详细了解细胞色素P450如何激活O2和NO。这些研究将与在非均相条件下的研究相补充，其中复合物将固定在电极表面上，并测试它们电催化还原O2（燃料电池技术）和活化C-H键（合成）的能力。

In this project funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Nicolai Lehnert of the Department of Chemistry at the University of Michigan will develop new classes of model systems for the active site of the Cytochrome P450 enzyme family. These enzymes play a key role in humans for the biosynthesis of steroids and the metabolism of drugs via the activation of inert C-H bonds, and are therefore of general interest for the pharmaceutical and chemical industry. The goal of this project is to build model systems that incorporate second coordination sphere effects of the protein matrix into the synthetic model systems. The new model systems will then be used to (a) explore the molecular mechanism of O2 and NO activation by Cytochrome P450s, and (b) develop Cytochrome P450 biomimics as catalysts for industrial applications, in particular for O2 reduction in fuel cells, and C-H bond activation of organic molecules. The project lies at the interface of inorganic, biological, and organic chemistry, and is therefore well suited to the education of scientists at all levels. This research group is also well-positioned to provide summer research internships for underrepresented minority high school students from the Detroit area. Due to the great potential of cytochrome P450 for practical applications, a number of model systems have previously been created to mimic the heme-thiolate active sites of cytochrome P450s. However, most of these biomimetic complexes degrade readily in the presence of O2 or NO, even in the ferric (resting) state. This unexpected lack of stability is due to a valence tautomerism, where the ferric thiolate ground state of these complexes is in equilibrium with the ferrous thiyl state at room temperature. Based on these findings, this research group plans to investigate a new series of heme-thiolate model complexes that contain (a) hydrogen-bond stabilized thiolate ligands, and (b) different types of picket fence porphyrins, where 2nd coordination sphere effects are incorporated into the distal pockets of the model systems. This new series of complexes will be used to systematically investigate the reactivity of heme-thiolate active sites with O2 and NO to obtain detailed insight into how Cytochrome P450s activate O2 and NO. These investigations will be complemented with studies under heterogeneous conditions where the complexes will be immobilized on electrode surfaces, and their ability to electrocatalytically reduce O2 (fuel cell technology) and activate C-H bonds (synthesis) will be tested.