Endocannabinoid Metabolic Enzymes: Structure, Function, In Vivo Inhibition

内源性大麻素代谢酶：结构、功能、体内抑制

• 批准号: 8279262
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 117.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279262
• 关键词: 2-arachidonylglycerol; Active Sites; Address; Anxiety; Behavior; Behavioral; Biochemical; Biochemical Pathway; CNR1 gene; Chemicals; Cognition; Communities; Complex; Degradation Pathway; Disease; Emotional; Endocannabinoids; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Esthesia; Ethanolamines; Genetic; Goals; Health; Human; Hydrolase; Inflammation; Instruction; Interdisciplinary Study; Knowledge; Lead; Lipids; Mental Depression; Metabolic; Metabolic Diseases; Metabolism; Methods; Nervous system structure; Pain; Pathway interactions; Peripheral; Physiological; Physiological Processes; Process; Proteomics; Research; Scientist; Signal Transduction; Structure; Therapeutic Agents; anandamide; behavioral pharmacology; chemical genetics; chronic pain; design; endogenous cannabinoid system; enzyme structure; experience; feeding; human disease; in vivo; inhibitor/antagonist; mutant; neurochemistry; neurophysiology; new therapeutic target; programs; three dimensional structure; tool

The endocannabinoids (ECs) A/-arachidonoyl ethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are lipid transmitters that activate the central and peripheral cannabinoid receptors (CB1 and CB2, respectively) to regulate a broad range of physiological processes, including pain sensation, inflammation, cognition, emotional state, and feeding. The magnitude and duration of EC signaling are tightly regulated by hydrolytic enzymes. However, our understanding of the distinct biochemical pathways that terminate AEA and 2-AG signaling in vivo remains incomplete. Key outstanding questions include: 1) what are the mechanisms and three-dimensional structures of EC hydrolases? 2) what are the neurochemical and physiological consequences of perturbing the function of EC hydrolases in vivo? 3) do multiple hydrolases coordinately control 2-AG metabolism in vivo? and 4) do AEA- and 2-AG-dependent EC pathways regulate distinct mammalian behaviors? In this Program Project, we have assembled a multidisciplinary research team that aims to address these questions by developing and implementing cutting-edge chemical, enzymological, genetic, proteomic, structural, and behavioral pharmacology methods. Specifically, we plan to: 1) characterize the biochemical and cellular mechanisms for terminating EC signaling the nervous system (Project 1), 2) determine the crystal structures of key EC hydrolases, including apo-enzymes, inhibitor complexes, and active-site mutants (Project 2), and 3) evaluate the neurochemical and behavioral effects of disrupting EC hydrolases in vivo (Projects 3 and 4). The knowledge gained from these studies will be further applied towards the design of increasingly potent and selective inhibitors of EC hydrolases (Core), which should prove of great value as both research tools and potential therapeutic agents for the treatment of a range of human diseases, including chronic pain, depression, anxiety, and metabolic disorders..

内源性大麻素 (EC) A/-花生四烯酰乙醇胺（anandamide，AEA）和 2-花生四烯酰甘油 (2-AG) 是激活中枢和外周大麻素受体（CB1 和 CB2， 分别）调节广泛的生理过程，包括痛觉、炎症、 认知、情绪状态和喂养。 EC 信号的强度和持续时间受到严格调节 水解酶。然而，我们对终止 AEA 的不同生化途径的理解 2-AG 体内信号传导仍然不完整。关键的悬而未决的问题包括：1）什么是 EC水解酶的机制和三维结构？ 2）什么是神经化学物质和 扰乱体内 EC 水解酶功能的生理后果？ 3) 进行多种水解酶 协调控制体内2-AG代谢？ 4) AEA 和 2-AG 依赖性 EC 通路是否调节 哺乳动物的独特行为？在这个项目中，我们汇集了多学科研究 旨在通过开发和实施尖端化学品来解决这些问题的团队， 酶学、遗传学、蛋白质组学、结构和行为药理学方法。具体来说，我们计划 目的：1) 表征终止 EC 信号传导的生化和细胞机制 系统（项目 1）、2）确定关键 EC 水解酶的晶体结构，包括脱辅基酶、 抑制剂复合物和活性位点突变体（项目 2）和 3）评估神经化学和行为 破坏体内 EC 水解酶的影响（项目 3 和 4）。从这些研究中获得的知识将 进一步应用于设计越来越有效和选择性的 EC 水解酶抑制剂（核心）， 作为研究工具和潜在的治疗药物，这应该被证明具有巨大的价值 一系列人类疾病，包括慢性疼痛、抑郁、焦虑和代谢紊乱。