Novel Structure and Function of Human Sirtuins

Abstract

Sirtuins are NAD–dependent deacetylases that regulate important biological processes. Four mammalian sirtuins (Sirt4 to Sirt7) have no detectable or very weak deacetylase activity. Using structural and biochemical data we have discovered that Sirt5 is an efficient desuccinylase and demalonylase in vitro, catalyzing the hydrolysis of succinyl and malonyl lysine residues. Furthermore, deletion of Sirt5 in mice increase the level of succinylation on carbamoyl phosphate synthase 1 (CPS1), a known target of Sirt5. Sirt5 is the first Sirtuin demonstrated to prefer an acyl group other than acetyl, suggesting that other Sirtuins showing little or no deacetylation activity may prefer to hydrolyze different acyl groups too [1]. We have also demonstrated that Sirt6 catalyzes the removal of long chain fatty acyl groups. Sirt6 promotes the secretion of tumor necrosis factor-α (TNFα) by removing the fatty acyl modification on this cytokine. The crystal structure of Sirt6 with a myristoyl peptide may pave a way for novel therapeutic interventions in the field of autoimmunity and inflammation [1]. [1] Du et al, Science, Vol. 334, 806-809 (2011). [2] Jiang et al, Nature, 496, 110–113 (2013).