Sirtuins are NAD+-dependent protein deacylases/ADP-ribosyltransferases that have emerged as candidate targets for new therapeutics to treat metabolic disorders and other diseases, including cancer. The sirtuin SIRT5 resides primarily in the mitochondrial matrix and catalyzes the removal of negatively charged lysine acyl modifications; succinyl, malonyl, and glutaryl groups. Evidence has now accumulated to document the roles of SIRT5 as a significant regulator of cellular homeostasis, in a context- and cell-type specific manner, as has been observed previously for other sirtuin family members. SIRT5 regulates protein substrates involved in glycolysis, the TCA cycle, fatty acid oxidation, electron transport chain, ketone body formation, nitrogenous waste management, and ROS detoxification, among other processes. SIRT5 plays pivotal roles in cardiac physiology and stress responses and is involved in the regulation of numerous aspects of myocardial energy metabolism. SIRT5 is implicated in neoplasia, as both a tumor promoter and suppressor in a context-specific manner, and may serve a protective function in the setting of neurodegenerative disorders. Here, we review the current understanding of functional impacts of SIRT5 on its metabolic targets, and its molecular functions in both normal and pathological conditions. Finally, we will discuss the potential utility of SIRT5 as a drug target and also summarize the current status, progress, and challenges in developing small molecule compounds to modulate SIRT5 activity with high potency and specificity.
Keywords: Succinylation; glutarylation; inhibitors; malonylation; mitochondria.