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Biochemical Mechanism of Eicosanoid Synthesizing Enzymes

类二十烷酸合成酶的生化机制

基本信息

批准号：
9237609
负责人：
Aditi Das
金额：
$ 30.13万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237609
关键词：
Acids Active Sites Amiodarone Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Binding Binding Proteins Biochemical Biochemistry CYP2J2 gene Cardiac Myocytes Cardiotoxicity Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cholesterol Complex Consumption Detection Diet Dietary Fatty Acid Doxorubicin Eicosanoids Electron Transport Electrostatics Endocannabinoids Environment Enzyme Interaction Enzymes Epithelium Epoxy Compounds Exhibits Exogenous Factors Fluorescence Spectroscopy Future Generations Goals Health Benefit Heart Homeostasis Human Inflammation Kinetics Link Linoleic Acids Lipids Literature Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Membrane Lipids Metabolism Methodology Methods Muscle Cells Omega-3 Fatty Acids Omega-6 Fatty Acids Outcome Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Physiological Play Positioning Attribute Process Proteins Role Solubility Spectrum Analysis Techniques Terfenadine Testing Thermodynamics Work aqueous cardiovascular health design fatty acid metabolism innovation lipid mediator nanodisk novel novel strategies therapeutic development therapeutic target

项目摘要

PROJECT SUMMARY Dietary consumption of ω-3 and ω-6 fatty acids have been linked to cardiovascular health benefits in humans. The central hypothesis is that the cardiovascular physiological effects of ω-3 and ω-6 fatty acids are partly mediated by the synthesis of eicosanoids via the epoxygenase (EPOX) pathway. Herein we perform biochemical studies of some of the key enzymes in these pathways. CYP2J2 is an enzyme in the EPOX pathway that is highly expressed in the cardiovascular system in the aortic epithelium and cardiomyocytes. CYP2J2's primary effects are facilitated via epoxidation of ω-3 and ω-6 fatty acids into epoxides that exert potent anti- inflammatory, vasodilatory and pro-angiogenic effects. CYP2J2 is also implicated in cardiotoxicity of drugs. Additionally, CYP2J2 is also a membrane bound protein and exhibit unique biochemical mechanisms that are poorly characterized and are the primary focus of the current proposal. Our first goal is to understand allosteric modulation of CYP2J2 epoxygenase activity by ω-3 and ω-6 fatty acids and selected cardiotoxic drugs (doxorubicin, ebastine and terfenadine). Our second goal is to examine the metabolism of ω-3 and ω-6 fatty acid derived endocannabinoids by CYP2J2. It is predicted that similar to ω-6 endocannabinoids, the ω-3 endocannabinoids are substrates for the EPOX enzymes producing novel bioactive epoxide mediators. The third goal is to examine how the composition of membranes effect CYP2J2 activity. We use several novel approaches that includes detection of lipid mediators with mass spectrometry, innovative methodologies such as Nanodiscs to solubilize CYP2J2 and provide membrane bilayer environment. We also introduce novel concepts of lipid-drug heterotropic interactions influencing the formation of the products of these enzymes. The long-term goal of this work is to understand the interplay of the formation of the eicosanoids from dietary fatty acids.

项目概要膳食中摄入 ω-3 和 ω-6 脂肪酸与心血管健康益处相关人类。中心假设是 ω-3 和 ω-6 脂肪酸对心血管的生理作用部分是通过环氧化酶 (EPOX) 途径合成类二十烷酸介导的。在此我们对这些途径中的一些关键酶进行生化研究。 CYP2J2 是一种酶 EPOX 通路在心血管系统的主动脉上皮细胞中高度表达，心肌细胞。 CYP2J2 的主要作用是通过将 ω-3 和 ω-6 脂肪酸环氧化成具有有效抗炎、血管舒张和促血管生成作用的环氧化物。 CYP2J2 也是与药物的心脏毒性有关。此外，CYP2J2 也是一种膜结合蛋白，并表现出独特的生化机制尚不清楚，是当前研究的主要焦点提议。我们的首要目标是了解 ω-3 对 CYP2J2 环氧化酶活性的变构调节和 ω-6 脂肪酸以及选定的心脏毒性药物（阿霉素、依巴斯汀和特非那定）。我们的第二个目标是检查 CYP2J2 对 ω-3 和 ω-6 脂肪酸衍生的内源性大麻素的代谢。这是预测与 ω-6 内源性大麻素类似，ω-3 内源性大麻素是 EPOX 的底物产生新型生物活性环氧化物介质的酶。第三个目标是检查构图如何膜的数量影响 CYP2J2 活性。我们使用几种新方法，包括检测脂质使用质谱法、创新方法（例如 Nanodiscs）来溶解 CYP2J2 的介质并提供膜双层环境。我们还介绍了脂质-药物异向性的新概念影响这些酶产物形成的相互作用。这项工作的长期目标目的是了解膳食脂肪酸形成类二十烷酸的相互作用。