对去乙酰化酶激活的催化作用和机制研究进展
Catalysis and mechanistic insights into sirtuin activation.
机构信息
Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
出版信息
Chembiochem. 2011 Jan 24;12(2):281-9. doi: 10.1002/cbic.201000434. Epub 2010 Nov 9.
Abstract
SIRT1 is a member of the Sir2 family of NAD(+)-dependent protein deacetylases. The central role of SIRT1 in multiple metabolic and age-related pathways has pushed SIRT1 to the forefront to discover small-molecule activators. Promising compounds, including resveratrol and SRT1720 have been reported, however, whether these compounds are direct activators and the mechanism by which they activate remains poorly defined. This review examines the current debate surrounding purported activators, and will focus on the assays used in screening compounds, sirtuin catalysis, and the mechanistic basis for their actions. We discuss the potential pathways of SIRT1 activation that could be exploited for the development of novel therapeutics for treating type II diabetes, neurodegeneration, and diseases associated with aging.
摘要
SIRT1 是 NAD(+) 依赖的蛋白去乙酰化酶 Sir2 家族的一员。SIRT1 在多种代谢和与年龄相关的途径中的核心作用将 SIRT1 推向了发现小分子激活剂的前沿。已经报道了有前途的化合物，包括白藜芦醇和 SRT1720，然而，这些化合物是否是直接的激活剂以及它们激活的机制仍未得到很好的定义。这篇综述审查了围绕所谓的激活剂的当前争论，并将重点讨论用于筛选化合物、去乙酰化酶催化以及它们作用的机制基础的测定方法。我们讨论了 SIRT1 激活的潜在途径，这些途径可用于开发治疗 II 型糖尿病、神经退行性疾病和与衰老相关疾病的新型治疗药物。
相似文献
1
Catalysis and mechanistic insights into sirtuin activation.对去乙酰化酶激活的催化作用和机制研究进展
Chembiochem. 2011 Jan 24;12(2):281-9. doi: 10.1002/cbic.201000434. Epub 2010 Nov 9.
2
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.SRT1720、SRT2183、SRT1460 和白藜芦醇不是 SIRT1 的直接激活剂。
J Biol Chem. 2010 Mar 12;285(11):8340-51. doi: 10.1074/jbc.M109.088682. Epub 2010 Jan 8.
3
Sirtuin 1 (SIRT1): the misunderstood HDAC.沉默调节蛋白1（SIRT1）：被误解的组蛋白去乙酰化酶。
J Biomol Screen. 2011 Dec;16(10):1153-69. doi: 10.1177/1087057111422103. Epub 2011 Nov 15.
4
Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.SIRT1的小分子激活剂可在体内复制由卡路里限制引发的信号通路。
BMC Syst Biol. 2009 Mar 10;3:31. doi: 10.1186/1752-0509-3-31.
5
A patent review of sirtuin activators: an update.一种组蛋白去乙酰化酶激活剂的专利研究进展：更新。
Expert Opin Ther Pat. 2012 Apr;22(4):355-67. doi: 10.1517/13543776.2012.669374. Epub 2012 Mar 9.
6
Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol.白藜芦醇对SIRT1活性的变构、底物依赖性刺激的结构基础。
Genes Dev. 2015 Jun 15;29(12):1316-25. doi: 10.1101/gad.265462.115.
7
Discovery and characterization of a new class of NAD-independent SIRT1 activators.发现并表征一类新型 NAD 非依赖的 SIRT1 激活剂。
Pharmacol Res. 2024 Aug;206:107296. doi: 10.1016/j.phrs.2024.107296. Epub 2024 Jul 4.
8
Biochemical effects of SIRT1 activators.SIRT1激活剂的生化效应。
Biochim Biophys Acta. 2010 Aug;1804(8):1626-34. doi: 10.1016/j.bbapap.2009.10.025. Epub 2009 Nov 6.
9
Small molecule SIRT1 activators for the treatment of aging and age-related diseases.小分子 SIRT1 激活剂治疗衰老和与年龄相关的疾病。
Trends Pharmacol Sci. 2014 Mar;35(3):146-54. doi: 10.1016/j.tips.2013.12.004. Epub 2014 Jan 16.
10
SIRT1-independent mechanisms of the putative sirtuin enzyme activators SRT1720 and SRT2183.推测的组蛋白脱乙酰酶激活剂 SRT1720 和 SRT2183 的 SIRT1 非依赖性机制。
Future Med Chem. 2010 Dec;2(12):1751-9. doi: 10.4155/fmc.10.257.
引用本文的文献
1
The Structures, Functions, and Roles of Class III HDACs (Sirtuins) in Neuropsychiatric Diseases.III 类组蛋白去乙酰化酶（Sirtuins）的结构、功能和在神经精神疾病中的作用。
Cells. 2024 Oct 2;13(19):1644. doi: 10.3390/cells13191644.
2
Obesity and Male Reproduction: Do Sirtuins Play a Role?肥胖与男性生殖：沉默调节蛋白是否发挥作用？
Int J Mol Sci. 2022 Jan 16;23(2):973. doi: 10.3390/ijms23020973.
3
Biophysical characterization of hit compounds for mechanism-based enzyme activation.基于机制的酶激活的命中化合物的物理化学特性分析。
PLoS One. 2018 Mar 16;13(3):e0194175. doi: 10.1371/journal.pone.0194175. eCollection 2018.
4
Lysine Deacetylases Exhibit Distinct Changes in Activity Profiles Due to Fluorophore Conjugation of Substrates.由于底物的荧光团共轭作用，赖氨酸脱乙酰酶的活性谱呈现出明显变化。
Biochemistry. 2017 Aug 29;56(34):4549-4558. doi: 10.1021/acs.biochem.7b00270. Epub 2017 Aug 16.
5
Epigenetic drug discovery: breaking through the immune barrier.表观遗传学药物研发：突破免疫屏障。
Nat Rev Drug Discov. 2016 Dec;15(12):835-853. doi: 10.1038/nrd.2016.185. Epub 2016 Oct 21.
6
Insights into Lysine Deacetylation of Natively Folded Substrate Proteins by Sirtuins.对去乙酰化酶介导的天然折叠底物蛋白赖氨酸去乙酰化作用的见解
J Biol Chem. 2016 Jul 8;291(28):14677-94. doi: 10.1074/jbc.M116.726307. Epub 2016 May 18.
7
The role of sirtuins in cellular homeostasis.沉默调节蛋白在细胞稳态中的作用。
J Physiol Biochem. 2016 Sep;72(3):371-80. doi: 10.1007/s13105-016-0492-6. Epub 2016 May 6.
8
Novel thiourea-based sirtuin inhibitory warheads.新型基于硫脲的沉默调节蛋白抑制弹头。
Bioorg Med Chem Lett. 2015 Aug 15;25(16):3319-24. doi: 10.1016/j.bmcl.2015.05.058. Epub 2015 May 30.
9
Epigenetic pathway targets for the treatment of disease: accelerating progress in the development of pharmacological tools: IUPHAR Review 11.疾病治疗的表观遗传途径靶点：加速药理学工具开发的进展：IUPHAR综述11
Br J Pharmacol. 2014 Nov;171(22):4981-5010. doi: 10.1111/bph.12848.
10
Measurement of sirtuin enzyme activity using a substrate-agnostic fluorometric nicotinamide assay.使用与底物无关的荧光烟酰胺测定法测量去乙酰化酶活性。
Methods Mol Biol. 2013;1077:167-77. doi: 10.1007/978-1-62703-637-5_11.
本文引用的文献
1
Transition state of ADP-ribosylation of acetyllysine catalyzed by Archaeoglobus fulgidus Sir2 determined by kinetic isotope effects and computational approaches.古菌火球菌 Sir2 催化的乙酰赖氨酸 ADP-核糖基化的过渡态通过动力学同位素效应和计算方法确定。
J Am Chem Soc. 2010 Sep 8;132(35):12286-98. doi: 10.1021/ja910342d.
2
SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator.小分子激活 SIRT1：酶与激活剂直接相互作用的动力学和生物物理证据。
J Biol Chem. 2010 Oct 22;285(43):32695-32703. doi: 10.1074/jbc.M110.133892. Epub 2010 Aug 11.
3
Resveratrol, sirtuins, and the promise of a DR mimetic.白藜芦醇、沉默调节蛋白和 DR 模拟物的前景。
Mech Ageing Dev. 2010 Apr;131(4):261-9. doi: 10.1016/j.mad.2010.02.007. Epub 2010 Feb 26.
4
GSK/Sirtris compounds dogged by assay artifacts.葛兰素史克/ Sirtris化合物受检测假象困扰。
Nat Biotechnol. 2010 Mar;28(3):185-6. doi: 10.1038/nbt0310-185.
5
DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1.DYRK1A 和 DYRK3 通过磷酸化和激活 SIRT1 促进细胞存活。
J Biol Chem. 2010 Apr 23;285(17):13223-32. doi: 10.1074/jbc.M110.102574. Epub 2010 Feb 18.
6
Sirtuin chemical mechanisms.沉默调节蛋白的化学机制。
Biochim Biophys Acta. 2010 Aug;1804(8):1591-603. doi: 10.1016/j.bbapap.2010.01.021. Epub 2010 Feb 2.
7
AMPK and SIRT1: a long-standing partnership?AMPK 与 SIRT1：长期的合作关系？
Am J Physiol Endocrinol Metab. 2010 Apr;298(4):E751-60. doi: 10.1152/ajpendo.00745.2009. Epub 2010 Jan 26.
8
Mammalian sirtuins: biological insights and disease relevance.哺乳动物的 sirtuins：生物学见解和疾病相关性。
Annu Rev Pathol. 2010;5:253-95. doi: 10.1146/annurev.pathol.4.110807.092250.
9
Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.抑癌基因 1 缺失可调节 SIRT1 的活性，并导致高脂饮食诱导的小鼠肝脏脂肪变性。
J Clin Invest. 2010 Feb;120(2):545-58. doi: 10.1172/JCI39319. Epub 2010 Jan 11.
10
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.SRT1720、SRT2183、SRT1460 和白藜芦醇不是 SIRT1 的直接激活剂。
J Biol Chem. 2010 Mar 12;285(11):8340-51. doi: 10.1074/jbc.M109.088682. Epub 2010 Jan 8.
Zotero 插件