Substrate specificity of SIRT1-catalyzed lysine Nε-deacetylation reaction probed with the side chain modified Nε-acetyl-lysine analogs

Peptides containing l-Nε-acetyl-lysine (l-AcK) or its side chain modified analogs were prepared and assayed using SIRT1, the prototypical human silent information regulator 2 (Sir2) enzyme. While previous studies showed that the side chain acetyl group of l-AcK can be extended to bulkier acyl groups for Sir2 (including SIRT1)-catalyzed lysine Nε-deacylation reaction, our current study suggested that SIRT1-catalyzed deacetylation reaction had a very stringent requirement for the distance between the α-carbon and the side chain acetamido group, with that found in l-AcK being optimal. Moreover, our current study showed that SIRT1 catalyzed the stereospecific deacetylation of l-AcK versus its d-isomer. The results from our current study shall constitute another piece of important information to be considered when designing inhibitors for SIRT1 and Sir2 enzymes in general.

Peptides containing l-Nε-acetyl-lysine (l-AcK) or its analogs (shown below) were prepared and employed to study the substrate specificity of SIRT1-catalyzed lysine Nε-deacetylation reaction.Figure optionsDownload as PowerPoint slide