Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

被引：512

作者：

Hubbard, Basil P. ^{[1
]}

Gomes, Ana P. ^{[1
,2
]}

Dai, Han ^{[3
]}

Li, Jun ^{[1
]}

Case, April W. ^{[3
]}

Considine, Thomas ^{[3
]}

Riera, Thomas V. ^{[3
]}

Lee, Jessica E. ^{[4
]}

Yen, Sook E. ^{[4
]}

Lamming, Dudley W. ^{[1
]}

Pentelute, Bradley L. ^{[5
]}

Schuman, Eli R. ^{[3
]}

Stevens, Linda A. ^{[6
]}

Ling, Alvin J. Y. ^{[1
]}

Armour, Sean M. ^{[1
]}

Michan, Shaday ^{[1
]}

Zhao, Huizhen ^{[7
]}

Jiang, Yong ^{[7
]}

Sweitzer, Sharon M. ^{[7
]}

Blum, Charles A. ^{[3
]}

Disch, Jeremy S. ^{[3
]}

Ng, Pui Yee ^{[3
]}

Howitz, Konrad T. ^{[8
]}

Rolo, Anabela P. ^{[2
,9
]}

Hamuro, Yoshitomo ^{[4
]}

Moss, Joel ^{[6
]}

Perni, Robert B. ^{[3
]}

Ellis, James L. ^{[3
]}

Vlasuk, George P. ^{[3
]}

Sinclair, David A. ^{[1
,10
]}

机构：

[1] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[2] Univ Coimbra, Dept Life Sci, Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal

[3] Sirtris, Cambridge, MA 02139 USA

[4] ExSAR Corp, Monmouth Jct, NJ 08852 USA

[5] MIT, Dept Chem, Cambridge, MA 02139 USA

[6] NHLBI, NIH, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA

[7] GlaxoSmithKline, Collegeville, PA 19426 USA

[8] BIOMOL Res Labs Inc, Plymouth Meeting, PA 19462 USA

[9] Univ Aveiro, Dept Biol, P-3810193 Aveiro, Portugal

[10] Univ New S Wales, Dept Pharmacol, Sydney, NSW 2052, Australia

来源：

SCIENCE | 2013年 / 339卷 / 6124期

基金：

加拿大自然科学与工程研究理事会;

关键词：

SMALL-MOLECULE ACTIVATORS; MITOCHONDRIAL-FUNCTION; DEACETYLASE ACTIVITY; RESVERATROL; SIRTUINS; SURVIVAL; TRANSCRIPTION; ACETYLATION; MODULATION; SRT1720;

D O I：

10.1126/science.1231097

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1 alpha and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.

引用

页码：1216 / 1219

页数：4

共 29 条

[1]

Resveratrol improves health and survival of mice on a high-calorie diet [J].

Baur, Joseph A. ;

Pearson, Kevin J. ;

Price, Nathan L. ;

Jamieson, Hamish A. ;

Lerin, Carles ;

Kalra, Avash ;

Prabhu, Vinayakumar V. ;

Allard, Joanne S. ;

Lopez-Lluch, Guillermo ;

Lewis, Kaitlyn ;

Pistell, Paul J. ;

Poosala, Suresh ;

Becker, Kevin G. ;

Boss, Olivier ;

Gwinn, Dana ;

Wang, Mingyi ;

Ramaswamy, Sharan ;

Fishbein, Kenneth W. ;

Spencer, Richard G. ;

Lakatta, Edward G. ;

Le Couteur, David ;

Shaw, Reuben J. ;

Navas, Placido ;

Puigserver, Pere ;

Ingram, Donald K. ;

de Cabo, Rafael ;

Sinclair, David A. .

NATURE, 2006, 444 (7117) :337-342

[2]

Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity [J].

Beher, Dirk ;

Wu, John ;

Cumine, Suzanne ;

Kim, Ki Won ;

Lu, Shu-Chen ;

Atangan, Larissa ;

Wang, Minghan .

CHEMICAL BIOLOGY & DRUG DESIGN, 2009, 74 (06) :619-624

[3]

Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein [J].

Bernier, Michel ;

Paul, Rajib K. ;

Martin-Montalvo, Alejandro ;

Scheibye-Knudsen, Morten ;

Song, Shaoming ;

He, Hua-Jun ;

Armour, Sean M. ;

Hubbard, Basil P. ;

Bohr, Vilhelm A. ;

Wang, Lili ;

Zong, Yaping ;

Sinclair, David A. ;

de Cabo, Rafael .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (22) :19270-19279

[4]

Mechanism of human SIRT1 activation by resveratrol [J].

Borra, MT ;

Smith, BC ;

Denu, JM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (17) :17187-17195

[5]

Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase [J].

Brunet, A ;

Sweeney, LB ;

Sturgill, JF ;

Chua, KF ;

Greer, PL ;

Lin, YX ;

Tran, H ;

Ross, SE ;

Mostoslavsky, R ;

Cohen, HY ;

Hu, LS ;

Cheng, HL ;

Jedrychowski, MP ;

Gygi, SP ;

Sinclair, DA ;

Alt, FW ;

Greenberg, ME .

SCIENCE, 2004, 303 (5666) :2011-2015

[6]

Sirtuins mediate mammalian metabolic responses to nutrient availability [J].

Chalkiadaki, Angeliki ;

Guarente, Leonard .

NATURE REVIEWS ENDOCRINOLOGY, 2012, 8 (05) :287-296

[7]

SIRT1 Activation by Small Molecules KINETIC AND BIOPHYSICAL EVIDENCE FOR DIRECT INTERACTION OF ENZYME AND ACTIVATOR [J].

Dai, Han ;

Kustigian, Lauren ;

Carney, David ;

Case, April ;

Considine, Thomas ;

Hubbard, Basil P. ;

Perni, Robert B. ;

Riera, Thomas V. ;

Szczepankiewicz, Bruce ;

Vlasuk, George P. ;

Stein, Ross L. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (43) :32695-32703

[8]

CBP/p300-mediated acetylation of histone H3 on lysine 56 [J].

Das, Chandrima ;

Lucia, M. Scott ;

Hansen, Kirk C. ;

Tyler, Jessica K. .

NATURE, 2009, 459 (7243) :113-U123

[9]

The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth [J].

Firestein, Ron ;

Blander, Gil ;

Michan, Shaday ;

Oberdoerffer, Philipp ;

Ogino, Shuji ;

Campbell, Jennifer ;

Bhimavarapu, Anupama ;

Luikenhuis, Sandra ;

de Cabo, Rafael ;

Fuchs, Charles ;

Hahn, William C. ;

Guarente, Leonard P. ;

Sinclair, David A. .

PLOS ONE, 2008, 3 (04)

[10]

Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α [J].

Gerhart-Hines, Zachary ;

Rodgers, Joseph T. ;

Bare, Olivia ;

Lerin, Carles ;

Kim, Seung-Hee ;

Mostoslavsky, Raul ;

Alt, Frederick W. ;

Wu, Zhidan ;

Puigserver, Pere .

EMBO JOURNAL, 2007, 26 (07) :1913-1923

← 1 2 3 →