NAD-dependent protein deacylase sirtuin-5 (SIRT5)

NAD-dependent protein deacylase sirtuin‑5 (SIRT5) is a member of the sirtuin family—class III histone deacetylases that require NAD+ as a cofactor. Primarily localized to mitochondria, SIRT5 catalyzes the removal of negatively charged acyl groups from lysine residues on substrate proteins. Its main enzymatic activities include desuccinylation, demalonylation, and deglutarylation; it has only weak classical deacetylase activity. Through these actions, SIRT5 regulates key aspects of cellular metabolism such as the urea cycle by activating carbamoyl phosphate synthetase 1 (CPS1), modulates oxidative stress response via superoxide dismutase activation, and influences ketogenesis. The physiological roles extend to neuroprotection and cardioprotection. In cancer biology, its function appears context dependent—acting either as tumor suppressor or promoter depending on tissue type or genetic background. Due to its central role in regulating mitochondrial metabolism and redox balance—and its involvement in diseases like cancer, cardiovascular disorders, and neurodegeneration—SIRT5 is considered an emerging therapeutic target. However, potent selective small-molecule modulators suitable for clinical use remain under development. No approved selective small-molecule inhibitors are currently available; research compounds exist but are not yet clinically established.

Other names

Sirtuin 5SIR2-like protein 5Regulatory protein SIR2 homolog 5SIR2L5

Inhibition or modulation of lysine deacylation activities, particularly desuccinylation, demalonylation, and deglutarylation on target proteins. Modulation can affect metabolic pathways and stress responses by altering post-translational modifications on key mitochondrial enzymes.