Sir2 regulation and chemical modulation

Sir2调节和化学调节

• 批准号: 7020948
• 负责人: ANTHONY A. SAUVE
• 金额: $ 31.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020948
• 关键词: acetylation; amidohydrolases; drug design /synthesis /production; drug screening /evaluation; enzyme activity; enzyme induction /repression; enzyme mechanism; nicotinamide; tissue /cell culture

DESCRIPTION (provided by applicant): The objective of the proposed research is to deduce mechanistic and regulatory principles that control the activities of sirtuin enzymes in yeast and human cells. These principles will be used to design small molecules that can activate sirtuins in cells. Sirtuins regulate a host of biologically significant activities including stress resistance, gene silencing and longevity. Sirtuins are implicated in mediating biological effects associated with calorie restriction. Calorie restriction has been shown to have numerous positive health benefits in mammals including reduced adipogenesis, insulin sensitivity and increased lifespan. These biological effects have raised interest in the enzymatic mechanisms of sirtuins, the means by which they are regulated in cells and the ways in which they might be modulated pharmacologically for improved human health. Sirtuins are NAD dependent deacetylases that remove acetyl-groups of acetyllysine modified histones and transcription factors thereby regulating chromatin and gene expression. We and others have demonstrated that these activities are regulated by NAD and nicotinamide levels in cells, and that the sirtuins are able to integrate information from energy and metabolic states to control genetic events. As part of our goal to better understand the functions of these enzymes and how they can be modulated in cells we propose to investigate the following specific aims: In Aim1 we propose to characterize the biochemical functions of this unique class of enzymes, emphasizing their chemical novelty and the incorporation of NAD in deacetylation reactions. In Aim2 we propose to show how enzymatic activity provides a mechanism for nicotinamide regulation of sirtuin activity. In addition with a recently developed mass spectrometry method we hope to gain new insights into how nicotinamide regulates sirtuins in cells. In Aim 3 we explore the development of small molecule activators of sirtuins designed from knowledge of the sirtuin reaction mechanism and the mechanism of nicotinamide regulation. These activators embody a novel approach to upregulate sirtuin action in cells and provide a potential entrypoint for pharmacological intervention to increase cell stress resistance and cell survival. Achievement of these aims is expected to provide new insights into the biochemistry and regulation of these enzymes, and provide proof of concept for new therapeutics that can activate sirtuins to treat diabetes and degenerative disorders.

描述（由申请人提供）：拟议的研究的目的是推论机械和调节原理，以控制酵母和人类细胞中sirtuin酶的活性。这些原理将用于设计可以激活细胞中Sirtuins的小分子。 Sirtuins调节许多具有生物学意义的活性，包括抗压力，基因沉默和寿命。 Sirtuins与介导与卡路里限制相关的生物学作用有关。卡路里限制已被证明在哺乳动物中具有许多积极的健康益处，包括脂肪生成降低，胰岛素敏感性和寿命增加。这些生物学作用引起了人们对Sirtuins的酶促机制的兴趣，Sirtuins的酶促机制在细胞中受到调节的手段以及可以在药理学上调节以改善人类健康的方式的方式。 Sirtuins是NAD依赖性的脱乙酰基酶，它去除乙酰透明苷修饰的组蛋白的乙酰基和转录因子，从而调节染色质和基因表达。我们和其他人表明，这些活性受细胞中NAD和烟酰胺水平调节，Sirtuins能够整合来自能量和代谢状态的信息以控制遗传事件。为了更好地了解这些酶的功能以及如何在细胞中调节它们的目标，我们建议研究以下特定目的：在AIM1中，我们建议表征这种独特的一类酶的生化功能，强调它们的化学新颖性，并在脱乙酰化反应中掺入NAD。在AIM2中，我们建议酶活性如何为SIRTUIN活性调节烟酰胺调节的机制。除了最近开发的质谱法之外，我们还希望获得有关烟酰胺如何调节细胞中Sirtuins的新见解。在AIM 3中，我们探讨了根据SIRTUIN反应机理的知识和烟酰胺调节机理设计的Sirtuins小分子活化剂的发展。这些激活剂体现了一种新的方法来上调细胞中的Sirtuin作用，并为药理学干预提供了潜在的入口点，以增加细胞应激抗性和细胞存活。预计这些目标的实现将为这些酶的生物化学和调节提供新的见解，并为可以激活Sirtuins治疗糖尿病和退化性疾病的新疗法提供概念证明。