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

金属酶的结构、功能以及作为神经变性和细菌发病机制的靶标

• 批准号: 10406916
• 负责人: THOMAS L POULOS
• 金额: $ 59.6万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406916
• 关键词: Address; Anabolism; Antibiotics; Binding; Biological; Biology; Catalysis; Complex; Coupled; Crystallization; Cytochrome P450; Development; Drug Metabolic Detoxication; Drug Targeting; Electron Transport; Enzymes; Goals; Heme; Hydrogen Peroxide; Investigation; Iron; Knowledge; Methicillin Resistance; Methods; Nature; Nerve Degeneration; Neurodegenerative Disorders; Nitric Oxide Synthase; Nitric Oxide Synthetase Inhibitor; Oxidation-Reduction; Oxides; Pathogenesis; Pathway interactions; Peroxidases; Peroxides; Play; Proteins; Protons; Reaction; Research; Role; Staphylococcus aureus; Structure; System; Testing; Therapeutic; Work; Xenobiotics; base; cofactor; design; drug metabolism; fundamental research; insight; metalloenzyme; oxidation; pathogenic bacteria; protein protein interaction; steroid metabolism; structural biology; therapeutic target

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.

血红素是生物学中最多样和最有用的含铁辅因子之一。之一 最多样化的功能是在氧化血红素酶中，其被设计为储存 氧化当量的H2O2或O2，以进行生物学上有用的氧化 反应.这些措施包括解毒有毒过氧化物和外源性物质（即药物 代谢）和各种生物合成中的小有机化合物的氧化 途径，如类固醇代谢和抗生素生物合成。结构生物学 在了解这些酶方面发挥了关键作用，普洛斯实验室已经 主要集中在过氧化物酶，细胞色素P450，一氧化氮， 合成酶（NOS）和电子转移所需的各种辅助蛋白。由于 由于氧化还原伴侣复合物的瞬时性质， 晶体结构，这就是为什么PDB中很少有。我们知识上的差距 在P450中尤其重要，其中氧化还原配偶体结合可以在以下方面发挥关键作用： 除了发挥关键的效应器作用之外， 用于质子耦合电子转移。众所周知的P450凸轮的最新进展 系统提供了关于氧化还原引起的结构变化的具体假设 伴侣结合是O2激活所必需的，并导致了对 P450如何工作的传统观点。这引起了广泛的讨论，一些 相当有争议，但也刺激了研究，以测试其中一些的有效性， 新的想法一个关键的问题正在解决的是一般性的氧化还原配偶体效应 控制在P450催化除了生物学基础，为什么这样的控制水平 有些P450是必需的，而其他的则不是。NOS是一款P450， 深入了解O2活化和底物氧化。NOS也被证明是一种 在神经变性疾病和某些致病性疾病中重要治疗靶点 耐甲氧西林金黄色葡萄球菌（MRSA）。与西尔弗曼实验室一起 在西北大学，基于结构的方法正在应用于开发 高选择性NOS抑制剂。总的来说，正在进行的各种项目提供了一个 血红素酶功能基础研究与 明确定义的生物医学相关性。