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

Bioorg Chem. 2010 Feb;38(1):17-25. doi: 10.1016/j.bioorg.2009.10.001. Epub 2009 Oct 24.

Abstract

Peptides containing L-N(epsilon)-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 N(epsilon)-deacylation reaction, our current study suggested that SIRT1-catalyzed deacetylation reaction had a very stringent requirement for the distance between the alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biocatalysis
  • Humans
  • Lysine / analogs & derivatives*
  • Lysine / chemistry
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Stereoisomerism
  • Substrate Specificity

Substances

  • Recombinant Proteins
  • SIRT1 protein, human
  • Sirtuin 1
  • Lysine