SIR2

The biochemical mehanism of NAD+-dependent protein deacetylation and ADP-ribosyl enzyme intermediates

Anthony A. Sauve, Vern L. Schramm

Research output: Contribution to journalArticle

62 Citations (Scopus)

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 organista. 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.

Original languageEnglish (US)
Pages (from-to)807-826
Number of pages20
JournalCurrent Medicinal Chemistry
Volume11
Issue number7
DOIs
StatePublished - Apr 2004

Fingerprint

NAD
Yeast
Adenosine Diphosphate
Genes
Caloric Restriction
Fungal Proteins
Genomic Instability
Osmotic Pressure
Gene Silencing
Enzymes
Saccharomyces cerevisiae
Hydrolysis
Proteins
Yeasts
Crystal structure
Substrates
2-O-acetyl-ADP-ribose

Keywords

  • Acetyl-ADP-ribose
  • ADP-ribose intermediates
  • CD38
  • Gene silencing
  • Lifespan
  • Longevity
  • Protein deacetylation
  • SIR2

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

SIR2 : The biochemical mehanism of NAD+-dependent protein deacetylation and ADP-ribosyl enzyme intermediates. / Sauve, Anthony A.; Schramm, Vern L.

In: Current Medicinal Chemistry, Vol. 11, No. 7, 04.2004, p. 807-826.

Research output: Contribution to journalArticle

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