Metalloenzyme structure, function, and as targets for neurodegeneration and bacterial pathogenesis

血红素是生物学中种类最多、用途最广的含铁辅因子之一。其中之一 最多样的功能是在氧化的血红素酶中，这种酶被设计成存储 氧化当量的过氧化氢或氧气，以进行生物上有用的氧化 反应。这些包括有毒的过氧物和外源物质(即药物)的解毒。 代谢)和各种生物合成中小有机化合物的氧化 类固醇代谢和抗生素生物合成等途径。结构生物学 在理解这些酶方面发挥了关键作用，Poulos实验室已经 主要但不完全集中在过氧化物酶、细胞色素P450、一氧化氮 合酶(NOS)，以及电子传递所需的各种辅助蛋白。欠款 由于氧化还原伙伴络合物的暂时性，一直很难确定 晶体结构，这就是为什么PDB中的晶体如此之少。我们知识上的这个鸿沟是 在P450中尤其重要，因为在P450中，氧化还原伙伴结合在 除了发挥关键的效应器作用外，还控制底物的氧化位置 用于质子耦合电子转移。著名的P450凸轮的最新进展 系统已经提供了关于氧化还原引起的结构变化的具体假设 激活O2所需的合作伙伴结合，并已导致对 关于P450如何工作的传统观点。这引发了相当大的讨论，一些人 相当有争议，但也刺激了测试其中一些方法的有效性的研究 新点子。正在解决的一个关键问题是氧化还原伙伴效应器的一般性 除了控制P450催化的生物学基础外，为什么会有这样的控制水平 某些P450是必需的，但其他P450不是必需的。NOS是一款P450，并提供了更深层次的 对氧气活化和底物氧化的洞察。事实证明，NOS也是一种 神经退行性疾病和某些致病因素的重要治疗靶点 耐甲氧西林金黄色葡萄球菌(MRSA)等细菌。与Silverman实验室一起 在西北大学，基于结构的方法正在被应用于开发 具有高度选择性的一氧化氮合酶抑制剂。总体而言，各种正在进行的项目提供了 血红素酶功能基础研究与已有研究的协同结合 明确定义的生物医学相关性。

Heme is one of the most diverse and useful iron-containing cofactors in biology. One of the most diverse functions are in oxidative heme enzymes that are designed to store the oxidizing equivalents of H2O2 or O2 in order to carry out biologically useful oxidation reactions. These include detoxification of toxic peroxides and xenobiotics (ie drug metabolism) and the oxidation of small organic compounds in various biosynthetic pathways such as in steroid metabolism and antibiotic biosynthesis. Structural biology has played a critical role in understanding these enzymes and the Poulos lab has focused primarily, but not exclusively, on peroxidases, cytochromes P450, nitric oxide synthase (NOS), and the various auxiliary proteins required for electron transfer. Owing to the transient nature of redox partner complexes, it has been difficult to determine crystal structures which is why there are so few in the PDB. This gap in our knowledge is especially important in P450s where redox partner binding can play a critical role in controlling where the substrate is oxidized in addition to exerting an effector role critical for proton coupled electron transfer. Recent advances in the well known P450cam system has provided specific hypotheses on the structural changes induced by redox partner binding that are required for O2 activation and has resulted in a rethinking of traditional views on how P450s work. This has generated considerable discussion, some quite controversial, but also has stimulated research to test the validity of some of these new ideas. A critical question being addressed is the generality of redox partner effector control in P450 catalysis in addition to the biological basis for why such a level of control is required for some P450s but not others. NOS is a P450 and has provided deeper insights into O2 activation and substrate oxidation. NOS also has proven to be an important therapeutic target in neurodegenerative diseases and in certain pathogenic bacteria like methicillin resistant Staph aureus (MRSA). Together with the Silverman lab at Northwestern, structure-based methods are being applied to the development of highly selective NOS inhibitors. Overall, the various ongoing projects provide a synergistic mix of fundamental research in heme enzyme function with research having clearly defined biomedical relevance.