Activation and Inhibition of Aldehyde Dehydrogenase 2

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，最显著的是乙醇代谢期间的乙醛，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，因为它能够通过产生细胞内一氧化氮来促进血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，酒精滥用的流行率略高于总人口的4.6%（约960万），而坦率的酒精依赖率略高于总人口的3.8%（约790万）[3]。美国国家心脏、肺和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，这使得该疾病的患病率略高于人口的2%。因此，有一个潜在的大部分美国人口，甚至更大的人口在世界上受到影响的进展，以提高我们的理解（S）醛脱氢酶在这方面发挥的作用。特别是，最近的研究表明，由于常见的多态性ALDH 2 *2，东亚人群中有很大一部分表现出GTN治疗疗效降低。我们实验室的结构研究表明，ALDH 2 *2变体中Glu 487被Lys（E487 K）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的结构完整性丧失。因此，该酶在体内基本上是无活性的，因为辅酶的细胞内浓度太低而不能支持乙醇代谢和GTN生物活化的活性。我们的合作者Daria Mochly-Rosen博士的实验室最近的工作，在我们实验室的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，可以恢复ALDH 2 *2变体的近野生型活性。以这作为一组新研究的基础，我们压倒一切的假设是ALDH 2中催化的独特方面，ALDH 2 *2等位基因的高患病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，这些药物将能够以受控方式操纵ALDH 2活性，以最大限度地改善特定疾病状态，同时最小化对ALDH 2参与的其它代谢途径的影响。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的很大一部分与醛脱氢酶（ALDH 2）催化这些底物代谢转化的能力有关。来自东亚人群的大约50%的个体具有醛脱氢酶的失活等位基因，该等位基因严重降低个体耐受酒精消耗的能力，因此对酒精中毒具有保护作用。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。本申请集中于开发ALDH 2活性的新型和选择性调节剂，使得与ALDH 2活性变化相关的特定结果可以最大化。

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.