title: SIRT1-independent mechanisms of the putative sirtuin enzyme activators SRT1720 and SRT2183.
abstract: BACKGROUND
  SRT1720 and SRT2183 were described recently as activators of the NAD+-dependent deacetylase, SIRT1. These molecules enhanced metabolic function when administered to rodents at doses of 100-500 mg/kg/day, purportedly by activating SIRT1 enzymatic activity in various tissues; however, considerable controversy surrounds these claims.
  
  
  RESULTS
  We find that these molecules do not activate SIRT1 deacetylase activity when tested in a variety of enzymatic assay formats and conditions. The compounds effectively decrease acetylated p53 in cells treated with DNA damaging agents but do so in cells that lack SIRT1, calling into question their designation as direct activators of SIRT1. In contrast, we find that the compounds inhibit p300 histone acetyltransferase activity in vitro, suggesting a possible mechanism for their effects in vivo.
  
  
  CONCLUSIONS
  Structural features of these molecules may account for false-positive activation using fluorescence-based assays.
authors.affiliation: Elixir Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Huber
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Peter S
authors.initials: PS
authors.lastname: Distefano
authors.forename: Thomas
authors.initials: T
authors.lastname: McDonagh
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D056564:Sirtuin 1 / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; C525423:SRT2183; D016159:Tumor Suppressor Protein p53; D056564:Sirtuin 1; D037761:Sirtuins