NAD-dependent protein lipoamidase sirtuin-4 (SIRT4)

NAD-dependent protein lipoamidase sirtuin-4 (SIRT4) is a mitochondrial enzyme belonging to the sirtuin family of NAD+-dependent deacylases. It plays a critical role in cellular energy sensing and metabolic homeostasis by regulating key enzymes through post-translational modifications, including ADP-ribosylation, deacetylation, and lipoamidation. SIRT4 primarily acts as a negative regulator of insulin secretion by inhibiting glutamate dehydrogenase (GDH) and suppresses glutamine metabolism, which often confers a tumor-suppressive role in various cancers. However, its biological impact is context-dependent, as it also inhibits fatty acid oxidation and can promote cell survival under specific genotoxic stress conditions. While SIRT4 is a promising therapeutic target for metabolic diseases and oncology, the development of selective pharmacological modulators is currently in the preclinical stage, with research focusing on small-molecule inhibitors and activators to fine-tune mitochondrial function.

Other names

Sirtuin 4SIR2L4SIR2-like protein 4NAD-dependent ADP-ribosyltransferase sirtuin-4NAD-dependent protein deacetylase sirtuin-4NAD-dependent protein biotinylase sirtuin-4

SIRT4 modulates target proteins through ADP-ribosylation, deacetylation, and delipoylation, thereby regulating metabolic flux in the mitochondria.