Activation and Inhibition of Aldehyde Dehydrogenase 2

描述(申请人提供)：线粒体形式的乙醛脱氢酶参与人类的多种代谢途径，包括内源性和生物性醛的代谢，最明显的是乙醇代谢过程中的乙醛，以及作为硝化甘油的生物激活剂。硝酸甘油或三硝酸甘油(GTN)是一种有效的血管扩张剂，因为它能通过产生细胞内一氧化氮来促进血管内平滑肌细胞的松弛。国家酒精滥用和酒精中毒研究所估计，酗酒的流行率仅占总人口的4.6%多一点(约960万)，赤裸裸的酒精依赖仅占总人口的3.8%多(约790万)[3]。美国国家心肺血液研究所和美国心脏协会估计，美国约有650万人患有心绞痛的一般症状，这使得这种疾病的患病率略高于总人口的2%。因此，很大一部分美国人口甚至世界上更多的人口可能会受到我们对(S)乙醛脱氢酶在这一领域所起作用的理解的进步的影响。特别是，最近的研究表明，由于常见的ALDH2*2多态，相当一部分东亚人群的GTN治疗效果降低。我们实验室的结构性工作表明，在ALDH2*2变异体中，Lys(E487K)取代Glu487影响活性的主要机制是通过辅酶结合和活性部位周围区域结构完整性的丧失。因此，这种酶在体内基本上是不活跃的，因为辅酶在细胞内的浓度太低，不能支持乙醇代谢和GTN的生物激活。我们的合作者Daria Mochly-Rosen博士的实验室最近的工作，以及我们实验室在酶学和结构生物学方面的贡献，已经确定了一种小分子激活剂，它可以恢复ALDH2*2变体的接近野生型的活性。以此作为一组新研究的基础，我们的压倒一切的假设是，ALDH2中催化的独特方面、ALDH2*2等位基因的高度流行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，使以受控方式操纵ALDH2的活性能够最大限度地使特定疾病状态受益，同时将对ALDH2参与的其他代谢途径的影响降至最低。公共卫生相关性：一个人代谢酒精的能力，以及对硝酸甘油治疗心绞痛症状的反应，很大一部分与乙醛脱氢酶(ALDH2)催化这些底物的代谢转化的能力有关。东亚人群中约50%的个体携带乙醛脱氢酶非活性等位基因，这种等位基因严重降低了个体对酒精消费的耐受能力，因此对酒精中毒具有保护作用。此外，同样的人群显示硝酸甘油在心绞痛治疗方案中的疗效降低。这项应用的重点是开发ALDH2活性的新型和选择性调节剂，以便最大化与ALDH2活性变化相关的特定结果。

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.