InterPro domain: IPR027546

The sirtuin (also known as Sir2) family is broadly conserved from bacteria to human. Yeast Sir2 (silent mating-type information regulation 2),the founding member, was first isolated as part of the SIR complex requiredfor maintaining a modified chromatin structure at telomeres. Sir2 functionsin transcriptional silencing, cell cycle progression, and chromosome stability[ 1 ]. Although most sirtuins in eukaryotic cells are located in the nucleus,others are cytoplasmic or mitochondrial.

This family is divided into five classes (I-IV and U) on the basis of a phylogenetic analysis of 60 sirtuins from a wide array of organisms [ 2 ]. Class I and class IV are further divided into three and two subgroups, respectively. The U-class sirtuins are found only in Gram-positive bacteria [ 3 ]. The S. cerevisiae genome encodes five sirtuins, Sir2 and four additional proteins termed 'homologues of sir two' (Hst1p-Hst4p) [ 3 ]. The human genome encodes seven sirtuins, with representatives from classes I-IV [ 3 , 3 ].

Sirtuins are responsible for a newly classified chemical reaction, NAD-dependent protein deacetylation. The final products of the reaction are thedeacetylated peptide and an acetyl ADP-ribose [ 4 ]. In nuclear sirtuinsthis deacetylation reaction is mainly directed against histones acetylatedlysines [ 5 ].

Sirtuins typically consist of two optional and highly variable N- and C-terminal domain (50-300 aa) and a conserved catalytic core domain (~250 aa).Mutagenesis experiments suggest that the N- and C-terminal regions helpdirect catalytic core domain to different targets [ 6 , 6 ].

The 3D-structure of an archaeal sirtuin in complex with NADreveals that the protein consists of a large domain having a Rossmann fold anda small domain containing a three-stranded zinc ribbon motif. NAD is bound ina pocket between the two domains [ 7 ].

This entry represents the Sirtuin family, class III subfamily. Proteins in this subfamily include the NAD-dependent protein deacylase sirtuin-5. Sirtuin-5 is the NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins [ 8 ].

1. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 9, 2888-902
2. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793-8
3. Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 5, 224
4. Chemistry of gene silencing: the mechanism of NAD+-dependent deacetylation reactions. Biochemistry 40, 15456-63
5. The molecular biology of the SIR proteins. Gene 279, 1-16
6. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 260, 273-9
7. Crystal structure of a SIR2 homolog-NAD complex. Cell 105, 269-79
8. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J. Mol. Biol. 382, 790-801