SIR2: the biochemical mechanism of NAD(+)-dependent protein deacetylation and ADP-ribosyl enzyme intermediates

Curr Med Chem. 2004 Apr;11(7):807-26. doi: 10.2174/0929867043455675.

Abstract

The Sir2 family of enzymes is a recently described class of NAD(+)-dependent protein deacetylases that use NAD+ as a reactant to deacetylate acetyllysine residues of protein substrates to form the aminolysine sidechain and a novel product 2'-O-acetyl-ADP-ribose. The founding member of the Sir2 proteins, the yeast Sir2p, has been identified as a key member of SIR complexes responsible for the long-term silencing of genes in the yeast Saccharomyces cerevisiae. Increase of Sir2 activity by caloric restriction or osmotic stress increases genome stability and lifespan in this organism. The Sir2 reaction mechanism couples ADP-ribosyltransfer and hydrolysis reactions via the formation of a stabilized ADPR-peptidyl intermediate. Principles of the chemistry of stabilized ADPR intermediates are examined for Sir2 and the mechanistically related ADP-ribosylcyclase CD38. An examination of the crystal structures of Sir2 family members is presented with a view to the chemical requirements of the Sir2 reaction. The present review describes the current knowledge of the Sir2 reaction, the reaction mechanism and the regulation of Sir2.

Publication types

  • Review

MeSH terms

  • ADP-ribosyl Cyclase / metabolism
  • ADP-ribosyl Cyclase 1
  • Acetylation
  • Adenosine Diphosphate Ribose / chemistry*
  • Adenosine Diphosphate Ribose / metabolism*
  • Antigens, CD / metabolism
  • Catalysis
  • Histone Deacetylases / chemistry*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histone Deacetylases / physiology
  • Hydrolysis
  • Kinetics
  • Models, Molecular
  • NAD / chemistry*
  • NAD / metabolism*
  • Niacinamide / metabolism
  • O-Acetyl-ADP-Ribose / biosynthesis
  • O-Acetyl-ADP-Ribose / metabolism
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Saccharomyces cerevisiae / enzymology
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / chemistry*
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / genetics
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / metabolism*
  • Sirtuin 2
  • Sirtuins / chemistry*
  • Sirtuins / genetics
  • Sirtuins / metabolism*

Substances

  • Antigens, CD
  • O-Acetyl-ADP-Ribose
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • NAD
  • Adenosine Diphosphate Ribose
  • Niacinamide
  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1
  • SIR2 protein, S cerevisiae
  • Sirtuin 2
  • Sirtuins
  • Histone Deacetylases