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The Chemistry and Biology of Sirtuin Enzymes
Author(s) -
Denu John M
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1474-a
Subject(s) - sirtuin , nad+ kinase , sirt3 , biochemistry , biology , nicotinamide adenine dinucleotide , acetylation , chemical biology , sirt2 , enzyme , microbiology and biotechnology , chemistry , gene
The Sir2 class (sirtuins) of proteins are linked to a wide range of biological functions, that include gene silencing, longevity, survival under stress, fatty acid metabolism, insulin secretion and mitochondrial function. Conserved among all forms of life, most sirtuins display robust NAD + ‐dependent protein deacetylase activity. Although genetic studies have provided insight into the pathways controlled by several sirtuins, the molecular basis for the observed biology remains elusive. Our lab has focused on understanding the biochemical basis for sirtuin biology. Sirtuins catalyzed the NAD + ‐dependent deacetylation of target proteins to yield products nicotinamide, deacetylated peptide and the novel metabolite, O ‐acetyl‐ADP‐ribose ( O AADPr), which has been proposed to act like a second‐messenger. We have examined the mechanisms of catalysis, nicotinamide inhibition, and acetyl‐peptide specificity. In addition, we have investigated the role of sirtuins in regulating fatty acid metabolism and have identified potential cellular targets of O AADPr. The emerging picture of sirtuin function suggests that the unique nature of this reaction allows these enzymes to tightly couple protein deacetylation and the cellular energy/redox state to the generation of O AADPr, a signaling molecule.