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）：醛脱氢酶的线粒体形式参与人类的多种代谢途径，包括内源性和生物源性醛的代谢，最著名的是乙醇代谢过程中的乙醇醛，以及作为nitrogloglogloglogloglycerincerincerincerincerincerin of Nitrogylycerincerin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，因为它能够通过产生细胞内一氧化氮来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，酒精滥用率的普遍性仅占普通人群的4.6％以上（约960万）和弗兰克酒精依赖的人口占人口的3.8％以上（约790万）[3]。国家心脏，肺和血液研究所以及美国心脏协会估计，美国约有650万人患有心绞痛的一般症状，这使该疾病的患病率刚刚超过2％。因此，有可能有很大一部分的美国人口，甚至在世界上更大的人口受到进步的影响，以提高我们对这一领域中醛脱氢酶发挥作用的理解。特别是，最近的研究表明，由于常见的多态性，ALDH2*2，东亚人口的很大一部分显示出GTN治疗的疗效降低。我们实验室中的结构性工作表明，LYS（E487K）在ALDH2*2变体中用Lys（E487K）取代GLU487的主要机制是通过在辅酶结合和活性位点周围的区域中失去结构完整性的。因此，酶在体内本质上是无活跃的，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。我们合作者Daria Mochly-Rosen博士的实验室的最新工作，在我们的实验室中贡献了酶学和结构生物学的贡献，已经确定了一个小分子激活剂，该激活剂可恢复ALDH2*2变体接近野生型活性。以此为基础进行了一系列研究的基础，我们的压倒性假设是，ALDH2中催化的独特方面，ALDH2*2等位基因及其在酒精代谢和心血管疾病中的作用的高度流行率将允许在选择性疾病中发现和设计ALDH2的效果，以使ALDH2的效果构成Maximimimize Maximize Maximize the Maximize Maximize Maximize Maximize Maximize the Maximize the Maximize the Maximize the Maximize and Maximize and Maximize and Maximize and a aldh2。 ALDH2参与的代谢途径。公共卫生相关性：很大一部分人代谢酒精的能力，以及对心绞痛症状的硝酸甘油治疗反应与醛脱氢酶（ALDH2）催化这些底物代谢转化的能力有关。东亚人群中约有50％的人具有醛脱氢酶的不活跃等位基因，可严重降低个人耐受酒精消耗的能力，因此对酒精中毒是保护性的。此外，同一人群显示硝酸甘油在心绞痛治疗方案中的疗效降低。该应用集中在ALDH2活性的新型和选择性调节剂的开发上，因此可以最大化与AldH2活性变化相关的特定结果。