SIRT4

Description

The SIRT4 (sirtuin 4) is a protein-coding gene located on chromosome 12.

Sirtuin 4, also known as SIRT4, is a mitochondrial protein encoded by the SIRT4 gene in humans. It is a member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT4 exhibits NAD+-dependent deacetylase activity. SIRT4 is a mitochondrial ADP-ribosyltransferase that inhibits mitochondrial glutamate dehydrogenase 1 activity, thereby downregulating insulin secretion in response to amino acids. Deacetylation of malonyl-CoA decarboxylase enzyme by SIRT4 represses the enzyme activity, inhibiting fatty acid oxidation in muscle and liver cells. SIRT4 has a suppressive effect on peroxisome proliferator-activated receptor alpha (PPAR-α) which downregulates fatty acid oxidation in liver cells. Deacetylation of ADP/ATP translocase 2 (ANT2) increases cellular ATP by dampening mitochondrial uncoupling. SIRT4 is a mitochondrial tumor suppressor protein. Overexpression of SIRT4 inhibits cancer cell proliferation by inhibition of glutamine metabolism.

SIRT4 acts as a NAD-dependent protein lipoamidase, biotinylase, deacetylase, and ADP-ribosyl transferase. It efficiently removes lipoyl and biotinyl modifications from proteins, and inhibits the pyruvate dehydrogenase complex (PDH) by hydrolyzing the lipoamide cofactor from its E2 component. It also catalyzes the transfer of ADP-ribosyl groups to target proteins, including mitochondrial GLUD1, inhibiting its activity. This makes SIRT4 a negative regulator of mitochondrial glutamine metabolism, expressed in response to DNA damage. By inhibiting GLUD1, it blocks glutamine metabolism into the tricarboxylic acid cycle and promotes cell cycle arrest. SIRT4 expression is repressed in response to mTORC1 signaling, promoting anaplerosis and cell proliferation. It acts as a tumor suppressor and mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity and regulating lipid homeostasis. It does not appear to deacetylate PC and controls fatty acid oxidation by inhibiting PPARA transcriptional activation. SIRT4 impairs SIRT1-PPARA interaction through regulating NAD(+) levels and downregulates insulin secretion.

SIRT4 is also known as SIR2L4.

Associated Diseases

WES Whole Exome Sequencing