Nε-Modified lysine containing inhibitors for SIRT1 and SIRT2
2010; Elsevier BV; Volume: 18; Issue: 15 Linguagem: Inglês
10.1016/j.bmc.2010.06.035
ISSN1464-3391
AutoresTero Huhtiniemi, Tiina Suuronen, Maija Lahtela‐Kakkonen, Tanja Bruijn, Sanna Jääskeläinen, Antti Poso, Antero Salminen, Jukka Leppänen, Elina M. Jarho,
Tópico(s)Adenosine and Purinergic Signaling
ResumoSirtuins catalyze the NAD+ dependent deacetylation of Nε-acetyl lysine residues to nicotinamide, O′-acetyl-ADP-ribose (OAADPR) and Nε-deacetylated lysine. Here, an easy-to-synthesize Ac-Ala-Lys-Ala sequence has been used as a probe for the screening of novel Nε-modified lysine containing inhibitors against SIRT1 and SIRT2. Nε-Selenoacetyl and Nε-isothiovaleryl were the most potent moieties found in this study, comparable to the widely studied Nε-thioacetyl group. The Nε-3,3-dimethylacryl and Nε-isovaleryl moieties gave significant inhibition in comparison to the Nε-acetyl group present in the substrates. In addition, the studied Nε-alkanoyl, Nε-α,β-unsaturated carbonyl and Nε-aroyl moieties showed that the acetyl binding pocket can accept rather large groups, but is sensitive to even small changes in electronic and steric properties of the Nε-modification. These results are applicable for further screening of Nε-acetyl analogues.
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