SIRT5
Description
The SIRT5 (sirtuin 5) is a protein-coding gene located on chromosome 6.
SIRT5, a member of the sirtuin family, is a protein encoded by the SIRT5 gene in humans. It is localized primarily to the mitochondria and exhibits enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing acetyl, succinyl, and malonyl groups from the lysine residues of proteins. SIRT5 deacetylates and regulates carbamoyl phosphate synthetase (CPS1), the rate-limiting step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity. Mice lacking SIRT5 show elevated ammonia levels after a prolonged fast, whereas mice overexpressing SIRT5 show increased CPS1 activity, suggesting one of the functions of SIRT5 may be to regulate the urea cycle. Alternative splicing of the SIRT5 gene results in two transcript variants, and the protein structure shows high conservation with other sirtuins.
SIRT5 is a NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins. It activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting. SIRT5 activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species. It activates SHMT2 by mediating its desuccinylation. SIRT5 modulates ketogenesis through the desuccinylation and activation of HMGCS2. SIRT5 has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. It can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX.
SIRT5 is also known as SIR2L5.
