Microsomal Cytochromes P450 and their Interactions with their Redox Partners

微粒体细胞色素 P450 及其与氧化还原伙伴的相互作用

基本信息

批准号：
8641389
负责人：
LUCY A WASKELL
金额：
$ 35.61万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641389
关键词：
Active Sites Address Alanine Anabolism Bile Acids Binding Binding Sites Biochemical Blood coagulation Carcinogens Cardiovascular system Catalysis Chemicals Cholesterol Clinical Collaborations Complex Cytochrome P450 Cytochromes b5 Development Drug Interactions Drug usage Eicosanoids Electron Nuclear Double Resonance Electronics Electrons Environmental Pollution Enzymes Estrogens Flavin Mononucleotide Freezing Goals High Pressure Liquid Chromatography Human Human Activities Hydrocortisone Hydroquinones In Vitro Individual Investigation Isoenzymes Knowledge LGLA Laboratories Length Life Light Lipids Lyase Mass Spectrum Analysis Measures Mechanics Mediating Membrane Metabolism Mixed Function Oxygenases Modeling Molecular Molecular Conformation Mothers Mutagenesis Mutate NADPH-Ferrihemoprotein Reductase Nature Organ Organism Oxidation-Reduction Oxidoreductase Pharmaceutical Preparations Physiological Processes Plants Polychlorinated Biphenyls Procedures Prodrugs Property Proteins Psychotropic Drugs Reaction Regulation Research Personnel Route Series Site-Directed Mutagenesis Steroids Substrate Specificity Surface Techniques Testing Testosterone Therapeutic Agents Toxic effect Vitamin D Xenobiotics base bisphenol A chemotherapeutic agent cytochrome b5 reductase design drug metabolism environmental agent flavin mononucleotide semiquinone human tissue hydroquinone in vivo insight member membrane activity mutant novel phthalates public health relevance quantum research study

项目摘要

DESCRIPTION (provided by applicant): The cytochrome P450 (cyt P450) superfamily consists of more than 11,000 members. They are ubiquitous, being found in all kingdoms of living organisms and plants and are referred to as Mother Nature's blowtorch, due to their ability to oxidize a vast number of stable chemical entities. Humans possess 56 different cyts P450, many of which are essential for early development and life itself. Other human cyts P450 determine the toxicity, duration of action, and elimination of the vast majority of therapeutic agents, carcinogens, and environmental agents to which humans are exposed. Xenobiotic metabolizing cyts P450 are also responsible for the majority of drug-drug interactions and adverse drug reactions. A third group of cyts P450 are responsible for the biosynthesis or metabolism of essential endogenous compounds. This includes virtually all steroids (cholesterol, bile acids, estrogens, testosterone, cortisol, and vitamin D) and many lipids and eicosanoids. Cyts P450 exists in virtually every organ and tissue of humans. The cyts P450 are not self-sufficient but rather require interactions with other proteins in order to function. Cyt P450 reductase and cytochrome b5 (cyt b5), which provide electrons to cyt P450, are two proteins that support the activity of cyt P450. The long-term goal of this project is to understand the structural and mechanistic basis for the regulation of the activity of the membrane-bound microsomal cyts P450 by its redox partners, cyt P450 reductase and cyt b5. The short-term goals of this proposal, using both human and model cyts P450, are to understand the biochemical basis of how the redox partners of cyt P450 regulate its activity, substrate specificity, and catalytic mechanism. Experimental techniques, including site-directed mutagenesis, rapid quenching of cyt P450 activity by chemical means, and freezing, HPLC-mass spectrometry, and quantum mechanical/molecular mechanical calculations will be employed to elucidate how the activity of microsomal cyts P450 is regulated by its redox partners. Understanding how nature designs cyt P450 active sites is a fundamental question with implications for predicting and eventually modifying the routes of metabolism of a large number of environmental contaminants such as phthalates, bisphenol A, polychlorinated biphenyls (PCBs) and many currently used drugs, including chemotherapeutic agents, psychoactive compounds, and cardiovascular therapies. Knowledge of the molecular mechanism by which the activity of human cyts P450 can be regulated will also prove to be a tremendous asset in developing drugs and procedures to alter the large number of critical physiologic processes in which the human cyts P450 participate, as well as in designing less toxic and more specific therapeutic agents and prodrugs, especially chemotherapeutic agents and environmental contaminants.

描述（由申请人提供）：细胞色素P450（CYT P450）超家族由11,000多名成员组成。它们无处不在，在所有生物体和植物的王国中都被发现，由于它们能够氧化大量稳定的化学实体，因此被称为大自然母亲的大自然。人类拥有56种不同的CYT P450，其中许多对于早期发展和生命本身至关重要。其他人类细胞P450决定了绝大多数治疗剂，致癌物和人类暴露的环境药物的毒性，作用持续时间和消除。异种生物代谢Cyts P450还负责大多数药物相互作用和不良药物反应。第三组CYTS P450负责基本内源性化合物的生物合成或代谢。这实际上包括所有类固醇（胆固醇，胆汁酸，雌激素，睾丸激素，皮质醇和维生素D）以及许多脂质和eicosanoids。 Cyts P450几乎存在于人类的每个器官和组织中。 Cyts P450不是自给自足的，而是需要与其他蛋白质相互作用才能发挥作用。 Cyt P450还原酶和细胞色素B5（Cyt B5）为Cyt P450提供电子，是两个支持Cyt P450活性的蛋白。该项目的长期目标是了解调节膜结合的微粒体Cyts P450的结构和机械基础，其氧化还原伙伴，Cyt P450还原酶和CytT B5。该提案的短期目标使用人类和模型Cyts P450，是为了了解Cyt P450的氧化还原伴侣如何调节其活性，底物特异性和催化机制的生化基础。实验技术，包括定位的诱变，化学方法对Cyt P450活性的快速淬火，冰冻，HPLC-MAS谱图以及量子力学/分子机械计算将如何阐明如何通过其氧化还原型伙伴调节微粒体Cyts P450的活性。 Understanding how nature designs cyt P450 active sites is a fundamental question with implications for predicting and eventually modifying the routes of metabolism of a large number of environmental contaminants such as phthalates, bisphenol A, polychlorinated biphenyls (PCBs) and many currently used drugs, including chemotherapeutic agents, psychoactive compounds, and cardiovascular therapies.了解可以调节人类CYT p450活性的分子机制的知识也将被证明是开发药物和程序的巨大资产，以改变人类Cyts P450参与的大量关键生理过程，以及设计毒性较低的毒性和更具体的治疗剂，尤其是毒品和produggs和Orthereprugs和Ortherepicational和Ortherepicational和Ortectimant和Ortherepicational和Ortherepicational和Ortherepicational和Ortectimant和Ortectimant和Envormation and overational和Otherapectication。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A single-site mutation (F429H) converts the enzyme CYP 2B4 into a heme oxygenase: a QM/MM study.

单位点突变 (F429H) 将 CYP 2B4 酶转化为血红素加氧酶：一项 QM/MM 研究。

DOI：
10.1021/ja211905e
发表时间：
2012
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Usharani,Dandamudi;Zazza,Costantino;Lai,Wenzhen;Chourasia,Mukesh;Waskell,Lucy;Shaik,Sason
通讯作者：
Shaik,Sason

How Do Perfluorinated Alkanoic Acids Elicit Cytochrome P450 to Catalyze Methane Hydroxylation? An MD and QM/MM Study.