Sirtuin 4 (SIRT4)

Sirtuin 4 is a mitochondrial enzyme and member of the sirtuin family, characterized by being a highly conserved NAD+-dependent deacylase and mono-ADP-ribosyltransferase[1][3][6][7]. Sirtuin 4 functions primarily to regulate metabolic processes, including fatty acid and amino acid metabolism, insulin secretion, and ATP homeostasis, by removing various posttranslational modifications (PTMs) from substrate proteins within mitochondria[1][3][6]. It exhibits weak deacetylase activity but robust substrate-specific deacylation, lipoamidase, and ADP-ribosyltransferase activities[1][3][6]. Sirtuin 4 plays important roles in suppressing tumorigenesis (notably in pancreatic and other cancers) by modulating glutamine metabolism, activating autophagy, and impacting signaling pathways such as p53[5]. Its functions are also implicated in neurodegeneration, cardiovascular and metabolic diseases, and aging[1][3][5][6]. Sirtuin 4 is widely expressed in mammalian tissues, with elevated levels in metabolically active organs such as the heart, liver, kidney, and muscle[3][6]. No drugs specifically targeting SIRT4 are clinically available, but its distinct enzymatic profile marks it as an emerging therapeutic target for metabolic, oncologic, and age-related diseases[1][2][6][7].

Other names

SIRT4Sir2-like protein 4Silent mating type information regulation 2 homolog 4Sirt4

Inhibition of Sirtuin 4 activity modulates its enzymatic effects on target proteins (e.g., increased activity of glutamate dehydrogenase promoting insulin secretion, altered fatty acid oxidation, altered pyruvate dehydrogenase activity)[1][2][3][7].Activation could enhance SIRT4’s suppression of glutamine metabolism and promotion of autophagy and tumor suppression[5].