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.