Abstract
Inhibitors of human NAD(+)-dependent protein deacetylases possess great value for deciphering the biology of these enzymes and as potential therapeutics for metabolic and age-related diseases and cancer. In the current study, we have experimentally demonstrated that, the potent inhibition we obtained previously for one of these enzymes (i.e. sirtuin type 1 (SIRT1)) by simply replacing N(epsilon)-thioacetyl-lysine for N(epsilon)-acetyl-lysine in its peptide substrate, represented a general and efficient strategy to develop potent and selective inhibitors of human NAD(+)-dependent protein deacetylase enzymes. Indeed, by using this simple inhibition strategy, potent (low-micromolar) and selective (< or =40-fold) SIRT2 and SIRT3 inhibitors, which were either comparable or superior to currently existing inhibitors, have also been quickly identified in the current study. These inhibitors could be used as chemical biological tools or as lead compounds for further focused structure-activity optimization.
Highlights
Reversible lysine Nε-acetylation on proteins has been increasingly recognized to play critical roles in regulating multiple pivotal cellular processes such as gene transcription, cell-cycle progression, and metabolism [1,2,3,4,5,6,7,8,9,10,11,12,13]
These peptides include peptides 1a-c that were used previously by us [18, 20] and others [21,22,23] for various studies; peptide 2 that was based on the template derived from the SIRT2 substrate human α-tubulin; and peptides 3a-c that were based on the template derived from the SIRT3 substrate human AceCS2
Peptides 1b and 1c were used, respectively, as the substrate and the synthetic authentic deacetylation peptide product for the SIRT1 inhibition assay based on high pressure liquid chromatography (HPLC) [18]
Summary
Reversible lysine Nε-acetylation on proteins has been increasingly recognized to play critical roles in regulating multiple pivotal cellular processes such as gene transcription, cell-cycle progression, and metabolism [1,2,3,4,5,6,7,8,9,10,11,12,13]. This reversible lysine Nε-acetylation is coordinated by protein acetyltransferases and protein deacetylases (Figure 1).
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