SIRT4 (sirtuin 4; HGNC:14932, NCBI Gene ID 23409) is a human locus mapped to chromosome band 12q24.31 that encodes mitochondrial matrix NAD+-dependent lipoamidase, deacylase & mono-ADP-ribosyltransferase Sirtuin 4 (314 aa; EC 2.4.2.30). SIRT4 acts in inhibition of glutamate dehydrogenase (GLUD1) & pyruvate dehydrogenase (PDH lipoamide cleavage) to restrain insulin secretion & tumor glutaminolysis, together with SIRT3 (Mitochondrial Deacetylase Paralog Gene), SIRT5 (Mitochondrial Desuccinylase Paralog Gene), and MTOR (mTORC1 Represses SIRT4 to Drive Glutaminolysis). Encodes the mitochondrial matrix sirtuin 4, which acts as a lipoamidase and ADP-ribosyltransferase restraining glutamate dehydrogenase, pyruvate dehydrogenase, and tumor glutaminolysis.
Inhibition of glutamate dehydrogenase (GLUD1) & pyruvate dehydrogenase (PDH lipoamide cleavage) to restrain insulin secretion & tumor glutaminolysis
Clinical / Therapeutic Role
Mitochondrial tumor suppressor repressed by mTORC1; DNA damage induces SIRT4 to halt glutamine anaplerosis into the TCA cycle
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 4-exon gene on chromosome 12q24.31 encoding a 314-amino-acid mitochondrial matrix enzyme with an N-terminal 28-residue mitochondrial targeting signal and a specialized catalytic channel that—unlike the deacetylase SIRT3—preferentially catalyzes NAD+-dependent mono-ADP-ribosylation, lipoamide cleavage (lipoamidase), and removal of branched-chain 3-hydroxy-3-methylglutaryl (HMG) and methylglutaconyl acyl groups.
Cellular & Tissue Expression Profile: Expressed in the mitochondrial matrix of pancreatic islet beta cells, hepatic hepatocytes, cardiac and skeletal myocytes, and vascular endothelial cells; unlike SIRT1 and SIRT3 (which are induced by fasting), basal SIRT4 is active in the fed state and is rapidly induced across tissues by genotoxic DNA damage while being transcriptionally repressed by hyperactive mTORC1-CREB2.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Performs three signature mitochondrial metabolic checkpoint functions: (1) mono-ADP-ribosylates and inhibits glutamate dehydrogenase (GLUD1), blunting amino-acid-stimulated insulin secretion in pancreatic beta cells and blocking glutamine anaplerosis into alpha-ketoglutarate; (2) acts as a cellular lipoamidase that cleaves the lipoamide cofactor from the DLAT (E2) subunit of the pyruvate dehydrogenase complex to gate acetyl-CoA entry into the TCA cycle; and (3) deacetylates and inhibits malonyl-CoA decarboxylase (MLYCD), elevating malonyl-CoA to restrain CPT1 fatty acid oxidation in the fed state while promoting leucine catabolism via MCCC activation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Functions as a potent mitochondrial tumor suppressor: upon DNA damage, cells up-regulate SIRT4 to arrest mitochondrial glutamine catabolism, preventing nucleotide synthesis and proliferation until DNA repair is completed; human lung, colorectal, breast, and gastric carcinomas frequently exhibit reduced SIRT4 expression, and Sirt4-knockout mice spontaneously develop lung, liver, and lymphoproliferative tumors.
Therapeutic & Clinical Pharmacology: Because mTORC1-driven and MYC-driven cancers repress SIRT4 to become addicted to mitochondrial glutaminolysis, reactivating SIRT4 or mimicking its blockade of GLUD1 is an active metabolic oncology strategy.