Sir2 regulation and chemical modulation
Sir2调节和化学调节
基本信息
- 批准号:8006734
- 负责人:
- 金额:$ 4.69万
- 依托单位:
- 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:
- 关键词:AbbreviationsAchievementAdenineAdenosine Diphosphate RiboseAnimalsApoptosisBindingBiochemicalBiochemistryBiologicalCaloric RestrictionCardiovascular DiseasesCatalysisCell SurvivalCellsCellular StressChemicalsChemistryChromatinDeacetylaseDeacetylationDegenerative DisorderDevelopmentDiabetes MellitusDinucleoside PhosphatesEnzymesEventGene ExpressionGene SilencingGeneticGoalsHealthHealth BenefitHistonesHumanInsulin ResistanceInterventionKnowledgeLongevityMammalian CellMammalsMass Spectrum AnalysisMediatingMetabolicMethodsMusNerve DegenerationNiacinamideNicotinamide MononucleotideNicotinamide adenine dinucleotideO-Acetyl-ADP-RiboseOrganismPatientsPeroxisome Proliferator-Activated ReceptorsProteinsReactionRegulationResearchResearch PersonnelResistanceRiboseSirtuinsStressTP53 geneTestingTherapeuticTissuesYeastsbasechemical reactionderepressiondesignhuman sirtuin 1improvedin vitro activityin vivoinsightinsulin sensitivityinterestisonicotinamidelipid biosynthesisnicotinatenicotinate mononucleotidenovel strategiesnovel therapeuticsprogramsresponsesmall moleculetranscription 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断控制的机制和调控原则
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:
- 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:
- 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。
- DOI:10.1016/j.mam.2013.01.004
- 发表时间:2013-12
- 期刊:
- 影响因子:10.6
- 作者:Canto, Caries;Sauve, Anthony A.;Bai, Peter
- 通讯作者:Bai, Peter
Sirtuin chemical mechanisms.
- DOI:10.1016/j.bbapap.2010.01.021
- 发表时间:2010-08
- 期刊:
- 影响因子:0
- 作者:Sauve AA
- 通讯作者:Sauve AA
Transition state of ADP-ribosylation of acetyllysine catalyzed by Archaeoglobus fulgidus Sir2 determined by kinetic isotope effects and computational approaches.
- DOI:10.1021/ja910342d
- 发表时间:2010-09-08
- 期刊:
- 影响因子:15
- 作者:Cen Y;Sauve AA
- 通讯作者:Sauve AA
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ANTHONY A. SAUVE其他文献
ANTHONY A. SAUVE的其他文献
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{{ truncateString('ANTHONY A. SAUVE', 18)}}的其他基金
NAD Metabolism in Aging and Disease: Dysfunction and Intervention
衰老和疾病中的 NAD 代谢:功能障碍和干预
- 批准号:
10259770 - 财政年份:2020
- 资助金额:
$ 4.69万 - 项目类别:
Nicotinamide Riboside and NAD+: Modulation of Sirtuins and Reactive Oxygen
烟酰胺核苷和 NAD:Sirtuins 和活性氧的调节
- 批准号:
8670002 - 财政年份:2013
- 资助金额:
$ 4.69万 - 项目类别:
Nicotinamide Riboside and NAD+: Modulation of Sirtuins and Reactive Oxygen
烟酰胺核苷和 NAD:Sirtuins 和活性氧的调节
- 批准号:
8483680 - 财政年份:2013
- 资助金额:
$ 4.69万 - 项目类别:
Nicotinamide Riboside and NAD+: Modulation of Sirtuins and Reactive Oxygen
烟酰胺核苷和 NAD:Sirtuins 和活性氧的调节
- 批准号:
8878303 - 财政年份:2013
- 资助金额:
$ 4.69万 - 项目类别:
Chemical Tools to Visualize Sirtuin Activity in Cells
可视化细胞中 Sirtuin 活性的化学工具
- 批准号:
8386178 - 财政年份:2012
- 资助金额:
$ 4.69万 - 项目类别:
Chemical Tools to Visualize Sirtuin Activity in Cells
可视化细胞中 Sirtuin 活性的化学工具
- 批准号:
8497684 - 财政年份:2012
- 资助金额:
$ 4.69万 - 项目类别:
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