SIRT5 (sirtuin 5; HGNC:14933, NCBI Gene ID 23408) is a human locus mapped to chromosome band 6p23 that encodes mitochondrial/cytosolic NAD+-dependent acidic-acyl deacylase Sirtuin 5 (310 aa; EC 2.3.1.B43). SIRT5 acts in removal of negatively charged malonyl, succinyl & glutaryl lysine modifications -> activation of CPS1 urea cycle, fatty acid oxidation & SOD1/IDH2, together with SIRT3 (Mitochondrial Deacetylase Paralog Gene), SIRT4 (Mitochondrial Lipoamidase Paralog Gene), and SOD1 (Cu/Zn Superoxide Dismutase Desuccinylated by SIRT5). Encodes the mitochondrial sirtuin 5 that removes negatively charged succinyl, malonyl, and glutaryl groups from metabolic and urea-cycle enzymes.
Detoxifies ammonia during fasting/high-protein diets via CPS1 activation & protects myocardium from ischemia-reperfusion injury
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 8-exon gene on chromosome 6p23 generating two main splice isoforms (310-residue mitochondrial isoform 1 and 299-residue isoform 2); its catalytic pocket contains two conserved positively charged residues—Tyr102 and Arg105—that form electrostatic salt bridges with negatively charged dicarboxylate acyl groups, giving SIRT5 negligible deacetylase activity but high catalytic efficiency as a lysine demalonylase, desuccinylase, and deglutarylase.
Cellular & Tissue Expression Profile: Abundantly expressed inside the mitochondrial matrix (with a secondary cytosolic/peroxisomal pool) of hepatic hepatocytes, cardiac myocytes, renal tubules, brown adipocytes, and brain neurons.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Because reactive acyl-CoA thioesters (malonyl-CoA, succinyl-CoA, glutaryl-CoA) non-enzymatically modify lysine residues across mitochondrial proteins and flip their charge from +1 to -1, SIRT5 uses NAD+ to strip these acidic marks (generating 2-prime-O-succinyl/malonyl/glutaryl-ADP-ribose): in the liver during fasting or high-protein feeding, SIRT5 deglutarylates and desuccinylates carbamoyl-phosphate synthetase 1 (CPS1), activating the rate-limiting step of the urea cycle to detoxify ammonia; in the heart and brown fat, SIRT5 desuccinylates SDHA, ECHA (HADHA), HMGCS2, and UCP1 to maintain fatty acid oxidation, ketogenesis, and thermogenesis; and in the cytosol/mitochondria it desuccinylates SOD1 and IDH2 to scavenge reactive oxygen species.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Loss of Sirt5 causes hyperammonemia during fasting, hypersuccinylation of cardiac mitochondrial proteins with age-related hypertrophic cardiomyopathy, and defective brown adipose cold thermogenesis.
Therapeutic & Clinical Pharmacology: Selective small-molecule SIRT5 activators and succinyl-mimetic inhibitors are under investigation to protect the myocardium against ischemia-reperfusion injury and to target SIRT5-dependent acute myeloid leukemia and melanoma subsets.