Catalysis and mechanistic insights into sirtuin activation.
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.
Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
Kristin E
KE
Dittenhafer-Reed
Jessica L
JL
Feldman
John M
JM
Denu
D000818:Animals; D055162:Biocatalysis; D006801:Humans; D011487:Protein Conformation; D056564:Sirtuin 1 / Q000378:metabolism*
D056564:Sirtuin 1
Nature. 2008 Jan 31;451(7178):583-6
18235501
EMBO J. 2004 Jun 16;23(12):2369-80
15152190
Biochem Biophys Res Commun. 2000 Jul 5;273(2):793-8
10873683
Chem Biol. 2003 Jan;10(1):61-8
12573699
Biochim Biophys Acta. 2010 Aug;1804(8):1591-603
20132909
J Am Chem Soc. 2010 Sep 8;132(35):12286-98
20718419
Chem Biol Drug Des. 2009 Dec;74(6):619-24
19843076
Nature. 2007 Nov 29;450(7170):712-6
18046409
Nat Struct Biol. 2003 Oct;10(10):864-71
14502267
Methods Enzymol. 2004;376:171-87
14975305
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3651-6
16697640
Dev Cell. 2008 May;14(5):661-73
18477450
Biochemistry. 2007 Dec 18;46(50):14478-86
18027980
Front Biosci (Landmark Ed). 2009 Jan 01;14(8):2983-95
19273250
Science. 2004 Mar 26;303(5666):2011-5
14976264
Nature. 2003 Sep 11;425(6954):191-6
12939617
J Biol Chem. 2002 Nov 22;277(47):45099-107
12297502
Biochim Biophys Acta. 2010 Aug;1804(8):1626-34
19897059
Nat Rev Mol Cell Biol. 2005 Apr;6(4):298-305
15768047
Biochem Biophys Res Commun. 2000 Nov 30;278(3):685-90
11095969
J Biol Chem. 2004 Dec 3;279(49):50754-63
15381699
Annu Rev Pathol. 2010;5:253-95
20078221
Mol Cell. 2007 Oct 26;28(2):277-90
17964266
Annu Rev Biochem. 2004;73:417-35
15189148
Int J Biochem Cell Biol. 2009 Nov;41(11):2125-8
19527796
Methods. 2005 Aug;36(4):332-7
16087348
Nature. 2008 Jan 31;451(7178):587-90
18235502
J Biol Chem. 2010 Mar 12;285(11):8340-51
20061378
Chem Biol. 2008 Oct 20;15(10):1002-13
18940661
FEBS J. 2005 Sep;272(18):4607-16
16156783
Mol Cell. 2005 Feb 18;17(4):595-601
15721262
Nature. 2009 Apr 23;458(7241):1056-60
19262508
J Biol Chem. 2010 Oct 22;285(43):32695-32703
20702418
Nat Rev Drug Discov. 2006 Jun;5(6):493-506
16732220
Cell. 2001 Oct 19;107(2):149-59
11672523
J Biol Chem. 2003 Dec 19;278(51):50985-98
14522996
PLoS One. 2009 Dec 22;4(12):e8414
20027304
Gene. 2001 Nov 14;279(1):1-16
11722841
Nat Cell Biol. 2007 Nov;9(11):1253-62
17934453
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8563-8
15150415
Methods. 2005 Aug;36(4):346-50
16085423
Genes Dev. 1999 Oct 1;13(19):2570-80
10521401
Nature. 2006 Nov 16;444(7117):337-42
17086191
J Biol Chem. 2009 Apr 17;284(16):10361-6
19218236
J Biol Chem. 2005 Apr 29;280(17):17038-45
15684413
PLoS One. 2008;3(12):e4020
19107194
Biochemistry. 2006 Jan 10;45(1):272-82
16388603
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14178-82
11106374
Curr Opin Chem Biol. 2008 Feb;12(1):11-7
18282481
Biochim Biophys Acta. 2010 Aug;1804(8):1666-75
19879981
Biochemistry. 2001 Dec 25;40(51):15456-63
11747420
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):415-20
11134535
Structure. 2008 Sep 10;16(9):1368-77
18786399
Am J Physiol Endocrinol Metab. 2010 Apr;298(4):E751-60
20103737
Anal Biochem. 2008 Jul 1;378(1):53-9
18358225
Aging Cell. 2007 Dec;6(6):759-67
17877786
Biochemistry. 2004 Aug 3;43(30):9877-87
15274642
Nat Biotechnol. 2010 Mar;28(3):185-6
20212464
Genetics. 1987 May;116(1):9-22
3297920
Mech Ageing Dev. 2007 Oct;128(10):546-52
17875315
Nature. 2005 Mar 3;434(7029):113-8
15744310
Nature. 2004 Aug 5;430(7000):686-9
15254550
J Biol Chem. 2010 Apr 23;285(17):13223-32
20167603
J Clin Invest. 2010 Feb;120(2):545-58
20071779
Mol Cell Biol. 1996 Aug;16(8):4349-56
8754835
Diabetes. 2006 Aug;55(8):2180-91
16873680
Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7217-22
17438283
IUBMB Life. 2008 May;60(5):323-32
18421779
J Biol Chem. 2007 Apr 13;282(15):10841-5
17307730
Bioorg Med Chem Lett. 2009 Apr 15;19(8):2350-3
19303289
Curr Opin Investig Drugs. 2008 Apr;9(4):371-8
18393104
J Med Chem. 2009 Sep 10;52(17):5496-504
19663498
Mech Ageing Dev. 2010 Apr;131(4):261-9
20219519
Cell. 2006 Sep 8;126(5):941-54
16959573
Proc Natl Acad Sci U S A. 2000 May 23;97(11):5807-11
10811920
Structure. 2006 Aug;14(8):1231-40
16905097
Mol Cell. 2004 Oct 8;16(1):93-105
15469825
J Biol Chem. 2002 May 24;277(21):18535-44
11893743
Oncogene. 2007 Aug 13;26(37):5528-40
17694092
Anal Biochem. 2009 Nov 1;394(1):101-9
19615966
Diabetes. 2010 Mar;59(3):554-63
19934007
J Biol Chem. 2005 Apr 29;280(17):17187-95
15749705