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Review
. 2011 Jan 24;12(2):281-9.
doi: 10.1002/cbic.201000434. Epub 2010 Nov 9.

Catalysis and mechanistic insights into sirtuin activation

Kristin E Dittenhafer-Reed  1 , Jessica L Feldman, John M Denu
Affiliations
Review

Catalysis and mechanistic insights into sirtuin activation

Kristin E Dittenhafer-Reed et al. Chembiochem. .

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.

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Figures

Figure 1
Figure 1
Crystal structure of Sir2Tm (PDB: 2H4F)[34] displaying the acetyl lysine poised for attack on C1' of the ribose ring of NAD+. Also highlighted is the conserved histidine residue proposed to act as the catalytic base in the second step of the mechanism.[25b]
Figure 2
Figure 2
Potential regulatory pathways of SIRT1 that could be exploited to increase SIRT1-mediated deacetylation. Phosphorylation, sumoylation, AMPK, small molecules, increased NAD+ levels and AROS binding are purposed activators (depicted in green). Nicotinamide, DBC1 binding, and de-sumoylation are purposed inhibitory pathways that could be regulated to increase SIRT1 activity (depicted in red). AMPK: AMP-activated kinase, AROS: Active regulator of SIRT1, DBC1: Deleted in breast cancer-1, NAM: Nicotinamide, NAMPT: Nicotinamide phosphoribosyltransferase, NMANT: Nicotinamide mononucleotide adenylyltransferase, OAADPr: O-Acetyl-ADP-ribose, SENP1: Sentrin specific protease 1, SUMO: Small ubiquitin-like modifier.
Scheme 1
Scheme 1
Substrates and products of the Sir2 (Sirtuins) catalyzed deacetylation reaction.
Scheme 2
Scheme 2
Proposed mechanism of Sir2 (Sirtuins) protein deacetylases.
Scheme 3
Scheme 3
Diagram of a fluorescence-based assay, like the Fluor de Lys (BIOMOL), displaying reactants and products of the reaction used to monitor Sirtuin activity.[2a, 36a] The p53-derived acetyl lysine peptide is covalently conjugated to a 7-amino-4-methylcoumarin (AMC) fluorophore. Deacetylation sensitizes the lysine residue to a trypsin developer that cleaves at the C-terminal end of deacetylated lysine and exposes the fluorescent tag resulting in an increase in fluorescent signal.
Scheme 4
Scheme 4
Structure of proposed SIRT1 activators.[2a, 4b, 26, 49]
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