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Sirtuins regulate metabolic adaptation to energy status
Author(s) -
Denu John Matthew,
Hallows William,
Smith Brian
Publication year - 2010
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.24.1_supplement.198.1
Subject(s) - sirtuin , acetylation , sirt2 , nad+ kinase , biochemistry , sirt3 , lysine , metabolic pathway , enzyme , biology , sirtuin 1 , glycolysis , chemistry , amino acid , gene , downregulation and upregulation
Reversible protein acetylation is now recognized as a major regulatory mechanism for controlling diverse cellular processes. With the recent cataloging of ~1000 acetylation sites on hundreds of proteins comes the challenge of assigning functional roles to specific lysine acetylation, of identifying the acetyltransferases and deaceytlases responsible, and of elucidating the physiological cause and effect. The sirtuin family of deacetylases represents a class of enzymes that are linked to a variety of metabolic pathways. Sirtuins catalyze NAD‐dependent conversion of epsilon‐amino acetylated lysine residues to deacetylated lysine, nicotinamide, and O‐acetyl‐ADP‐ribose. Previously, we have shown that acetyl‐CoA synthetases are regulated by Sirt1‐ and Sirt3‐dependent deacetylation, resulting in modulation of acetate/acetyl‐CoA metabolism. To identify other novel substrates and pathways controlled by sirtuins, we have utilized a multifaceted molecular approach involving metabolomic analysis of tissues from knockout mice, protein acetylome analysis, enzyme kinetics and a new high throughput screening strategy that takes advantage of the sirtuin catalytic mechanism. Collectively, these data reveal that sirtuins regulate an unexpectedly broad range of metabolic pathways that include glycolysis, fatty acid oxidation, and the urea cycle.