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）：拟议研究的目的是推导控制酵母和人类细胞中沉默调节蛋白酶活性的机制和调节原则。这些原理将用于设计能够激活细胞中sirtuins的小分子。Sirtuins调节许多生物学上重要的活动，包括胁迫抗性、基因沉默和寿命。Sirtuins参与介导与卡路里限制相关的生物学效应。热量限制已被证明对哺乳动物有许多积极的健康益处，包括减少脂肪生成，胰岛素敏感性和延长寿命。这些生物学效应引起了人们对sirtuins的酶机制的兴趣，它们在细胞中调节的方式以及它们可能被调节以改善人类健康的方式。Sirtuins是NAD依赖性脱乙酰酶，其去除乙酰基赖氨酸修饰的组蛋白和转录因子的乙酰基，从而调节染色质和基因表达。我们和其他人已经证明，这些活动受到细胞中NAD和烟酰胺水平的调节，并且sirtuins能够整合来自能量和代谢状态的信息以控制遗传事件。作为我们目标的一部分，以更好地了解这些酶的功能，以及它们如何在细胞中被调制，我们建议调查以下具体目标：在Aim 1中，我们建议表征这类独特的酶的生化功能，强调其化学新奇和NAD在脱乙酰反应中的掺入。在Aim2中，我们建议显示酶活性如何提供烟酰胺调节沉默调节蛋白活性的机制。此外，通过最近开发的质谱法，我们希望获得有关烟酰胺如何调节细胞中sirtuins的新见解。在目标3中，我们探索了从沉默调节蛋白反应机制和烟酰胺调节机制的知识设计的沉默调节蛋白的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沉默调节蛋白在细胞中的作用，并提供了一个潜在的切入点，药理学干预，以增加细胞的抗应激性和细胞存活。这些目标的实现有望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以治疗糖尿病和退行性疾病的新疗法提供概念证明。