Activation and Inhibition of Aldehyde Dehydrogenase 2

醛脱氢酶 2 的激活和抑制

基本信息

批准号：
7890708
负责人：
THOMAS D. HURLEY
金额：
$ 6.46万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7890708
关键词：
Acetaldehyde Active Sites Adjuvant Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Aldehydes Alleles American Heart Association Area Asians Basic Science Binding Biological Assay Cardiovascular Diseases Catalysis Cell Line Cell model Chemistry Coenzymes Collaborations Dependence Development Disease Enzymatic Biochemistry Enzymes Ethanol Metabolism Exhibits Future General Population Generations Genetic Polymorphism Glycerol High Prevalence Human Individual Institutes Kinetics Laboratories Lead Measures Metabolic Metabolic Pathway Metabolism Mitochondria Molecular National Heart, Lung, and Blood Institute Nitric Oxide Nitroglycerin Outcome Oxidoreductase Physiological Play Population Prevalence Production Property Reaction Relaxation Reporter Role Smooth Muscle Myocytes Solutions Structure Structure-Activity Relationship Symptoms Treatment Protocols Universities Variant Vasodilator Agents Work aldehyde dehydrogenases analog base daidzin design esterase high throughput screening improved in vivo inhibitor/antagonist medical schools novel oxidation public health relevance small molecule structural biology therapy design

项目摘要

DESCRIPTION (provided by applicant): The mitochondrial form of aldehyde dehydrogenase participates in multiple metabolic pathways in humans, including the metabolism of endogenous and biogenic aldehydes, most notably acetaldehyde during ethanol metabolism, and as the bioactivator of nitroglycerin. Nitroglycerin or glycerol trinitrate (GTN) is a potent vasodilator due to its ability to promote the relaxation of smooth muscle cells in the vasculature through the generation of intracellular nitric oxide. The National Institute of Alcohol Abuse and Alcoholism estimates the prevalence of alcohol abuse at just over 4.6% of the general population (~9.6 million) and of frank alcohol dependency at just over 3.8% of the population (~7.9 million) [3]. The National Heart, Lung and Blood Institute and the American Heart Association estimate that approximately 6.5 million people in the US suffer from the general symptoms of angina, which puts the prevalence of the disease just over 2% of the population. Thus, there is a potential for a large fraction of the US population and even larger population in the world to be impacted by progress toward improving our understanding of the role(s) aldehyde dehydrogenase plays in this area. In particular, recent studies have demonstrated that a significant fraction of the East Asian population exhibit reduced efficacy of GTN treatment due to the common polymorphism, ALDH2*2. Structural work in our laboratory has shown that the principal mechanism by which the substitution of Glu487 by Lys (E487K) in the ALDH2*2 variant affects activity is through a loss of structural integrity in the areas surrounding the coenzyme-binding and active sites. Consequently, the enzyme is essentially inactive in vivo because the intracellular concentrations of the coenzyme are too low to support activity for ethanol metabolism and GTN bioactivation. Recent work in the laboratory of our collaborator Dr. Daria Mochly-Rosen, with contributions in enzymology and structural biology from our laboratory, has identified a small molecule activator that restores near wild-type activity to the ALDH2*2 variant. With this as the basis for a new set of studies, our overriding hypothesis is that the unique aspects of catalysis in ALDH2, the high prevalence of the ALDH2*2 allele and their roles in alcohol metabolism and cardiovascular disease will permit the discovery and design of selective agents that will enable the manipulation of ALDH2 activity in a controlled manner to maximize the benefit to specific disease states, while minimizing the impact to other metabolic pathways in which ALDH2 participates. PUBLIC HEALTH RELEVANCE: A large fraction of one's ability to metabolize alcohol, as well as to respond to nitroglycerin treatment for the symptoms of angina is related to the ability of aldehyde dehydrogenase (ALDH2) to catalyze the metabolic conversions of these substrates. Approximately 50% of individuals from East Asian populations harbor an inactive allele of aldehyde dehydrogenase that severely reduces an individual's ability to tolerate alcohol consumption and is, thus, protective for alcoholism. In addition, this same population shows reduced efficacy of nitroglycerin in angina treatment regimens. This application is focused on the development of novel and selective modulators of ALDH2 activity such that specific outcomes associated with changes in ALDH2 activity can be maximized.

描述（由申请人提供）：线粒体形式的醛脱氢酶参与人体的多种代谢途径，包括内源性和生物源性醛的代谢，最显着的是乙醇代谢过程中的乙醛，以及作为硝酸甘油的生物活化剂。硝酸甘油或三硝酸甘油 (GTN) 是一种有效的血管扩张剂，因为它能够通过细胞内一氧化氮的生成促进脉管系统中平滑肌细胞的松弛。美国国家酒精滥用和酒精中毒研究所估计，总人口中酒精滥用的患病率略高于 4.6%（约 960 万），而直接酒精依赖的患病率略高于总人口的 3.8%（约 790 万）[3]。美国国家心肺血液研究所和美国心脏协会估计，美国大约有 650 万人患有心绞痛的一般症状，这使得该疾病的患病率略高于人口的 2%。因此，随着我们对醛脱氢酶在这一领域的作用的了解不断加深，美国的很大一部分人口甚至世界上更多的人口可能会受到影响。特别是，最近的研究表明，由于常见的多态性 ALDH2*2，很大一部分东亚人群表现出 GTN 治疗疗效下降。我们实验室的结构工作表明，ALDH2*2 变体中 Glu487 被 Lys (E487K) 取代影响活性的主要机制是通过辅酶结合和活性位点周围区域结构完整性的丧失。因此，该酶在体内基本上没有活性，因为辅酶的细胞内浓度太低，无法支持乙醇代谢和 GTN 生物活化的活性。我们的合作者 Daria Mochly-Rosen 博士的实验室最近在我们实验室的酶学和结构生物学方面做出了贡献，发现了一种小分子激活剂，可以恢复 ALDH2*2 变体接近野生型的活性。以此作为一系列新研究的基础，我们最重要的假设是 ALDH2 催化的独特方面、ALDH2*2 等位基因的高流行率及其在酒精代谢和心血管疾病中的作用将允许发现和设计选择性药物能够以受控方式操纵 ALDH2 活性，最大限度地提高对特定疾病状态的益处，同时最大限度地减少对 ALDH2 参与的其他代谢途径的影响。公共健康相关性：一个人代谢酒精以及对硝酸甘油治疗心绞痛症状的反应的能力很大一部分与乙醛脱氢酶 (ALDH2) 催化这些底物代谢转化的能力有关。大约 50% 的东亚人群携带乙醛脱氢酶失活等位基因，该基因严重降低了个体耐受饮酒的能力，因此可以预防酗酒。此外，同一人群中硝酸甘油在心绞痛治疗方案中的疗效也有所降低。该应用的重点是开发 ALDH2 活性的新型选择性调节剂，以便最大限度地提高与 ALDH2 活性变化相关的特定结果。