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Sir2 regulation and chemical modulation

Sir2调节和化学调节

基本信息

批准号：
8006734
负责人：
ANTHONY A. SAUVE
金额：
$ 4.69万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2009-12-31 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8006734
关键词：
Abbreviations Achievement Adenine Adenosine Diphosphate Ribose Animals Apoptosis Binding Biochemical Biochemistry Biological Caloric Restriction Cardiovascular Diseases Catalysis Cell Survival Cells Cellular Stress Chemicals Chemistry Chromatin Deacetylase Deacetylation Degenerative Disorder Development Diabetes Mellitus Dinucleoside Phosphates Enzymes Event Gene Expression Gene Silencing Genetic Goals Health Health Benefit Histones Human Insulin Resistance Intervention Knowledge Longevity Mammalian Cell Mammals Mass Spectrum Analysis Mediating Metabolic Methods Mus Nerve Degeneration Niacinamide Nicotinamide Mononucleotide Nicotinamide adenine dinucleotide O-Acetyl-ADP-Ribose Organism Patients Peroxisome Proliferator-Activated Receptors Proteins Reaction Regulation Research Research Personnel Resistance Ribose Sirtuins Stress TP53 gene Testing Therapeutic Tissues Yeasts base chemical reaction derepression design human sirtuin 1 improved in vitro activity in vivo insight insulin sensitivity interest isonicotinamide lipid biosynthesis nicotinate nicotinate mononucleotide novel strategies novel therapeutics programs response small molecule transcription factor

项目摘要

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 actvitities 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.

拟议研究的目的是推导出机制和监管原则，控制在酵母和人类细胞中的sirtuin酶的活性。这些原则将用于设计小型可以激活细胞中的沉默调节蛋白的分子。Sirtuins调节许多生物学上重要的活动包括抗逆、基因沉默和长寿。Sirtuins参与介导生物学与卡路里限制有关的影响。热量限制已经被证明有许多积极的对哺乳动物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的酶促机制的兴趣，sirtuins的酶促机制是它们在细胞中受到调节，并且它们可能被调节的方式可以改善细胞的功能。人体健康Sirtuins是NAD依赖性脱乙酰酶，其去除乙酰赖氨酸修饰的乙酰基。组蛋白和转录因子，从而调节染色质和基因表达。我们和其他人已经表明这些活性受细胞中NAD和烟酰胺水平的调节，去乙酰化酶能够整合来自能量和代谢状态的信息以控制遗传事件。一部分我们的目标是更好地了解这些酶的功能，以及它们如何在细胞中被调节，建议调查以下具体目标：在目标1中，我们建议表征生物化学这类独特的酶的功能，强调其化学新奇和NAD的掺入在脱乙酰化反应中。在Aim 2中，我们提出要展示酶活性如何提供一种机制，烟酰胺调节沉默调节蛋白活性。此外，最近开发的质谱法我们希望能对烟酰胺如何调节细胞中的sirtuins获得新的见解。在目标3中，我们探索根据去乙酰化酶反应的知识设计的去乙酰化酶的小分子活化剂的开发机制和烟酰胺调节机制。这些活化剂体现了一种新的方法，在细胞中上调沉默调节蛋白的作用，并为药理学干预提供潜在的切入点，增加细胞抗应激性和细胞存活。这些目标的实现，将提供新的深入了解这些酶的生物化学和调节，并为新的可以激活sirtuins以治疗糖尿病和退行性疾病的治疗剂。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Plasmodium falciparum Sir2 is an NAD+-dependent deacetylase and an acetyllysine-dependent and acetyllysine-independent NAD+ glycohydrolase.

DOI：
10.1021/bi800767t
发表时间：
2008-09-23
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
French, Jarrod B.;Cen, Yana;Sauve, Anthony A.
通讯作者：
Sauve, Anthony A.

Nicotinamide riboside kinase structures reveal new pathways to NAD+.

DOI：
10.1371/journal.pbio.0050263
发表时间：
2007-10-02
期刊：
PLOS BIOLOGY
影响因子：
9.8
作者：
Tempel, Wolfram;Rabeh, Wael M;Bogan, Katrina L;Belenky, Peter;Wojcik, Marzena;Seidle, Heather F;Nedyalkova, Lyudmila;Yang, Tianle;Sauve, Anthony A;Park, Hee-Won;Brenner, Charles
通讯作者：
Brenner, Charles

Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes.

聚（ADP-核糖）聚合酶和沉默调节蛋白酶之间的串扰。