Sirtuin 4

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AliasesSIRT4, SIR2L4, sirtuin 4
External IDsOMIM: 604482 MGI: 1922637 HomoloGene: 8164 GeneCards: SIRT4
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 12: 120.3 – 120.31 MbChr 5: 115.48 – 115.48 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Sirtuin 4, also known as SIRT4, is a mitochondrial protein which in humans is encoded by the SIRT4 gene.[5][6] SIRT4 is 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.[7] A deacetylation of malonyl-CoA decarboxylase enzyme by SIRT4 represses the enzyme activity, inhibiting fatty acid oxidation in muscle and liver cells.[8][9] SIRT4 has a suppressive effect on peroxisome proliferator-activated receptor alpha (PPAR-α) which downregulates fatty acid oxidation in liver cells.[9] Deacetylation of ADP/ATP translocase 2 (ANT2) increases cellular ATP by dampening mitochondrial uncoupling.[9]

Clinical significance[edit]

SIRT4 is a mitochondrial tumor suppressor protein.[9] Overexpression of SIRT4 inhibits cancer cell proliferation by inhibition of glutamine metabolism.[9][10]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000089163 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029524 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Frye RA (June 1999). "Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity". Biochem. Biophys. Res. Commun. 260 (1): 273–79. doi:10.1006/bbrc.1999.0897. PMID 10381378.
  6. ^ "Entrez Gene: Sirtuin 4".
  7. ^ Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L (September 2006). "SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells". Cell. 126 (5): 941–54. doi:10.1016/j.cell.2006.06.057. PMID 16959573. S2CID 1391160.
  8. ^ Nasrin N, Wu X, Fortier E, Feng Y, Bare' OC, Chen S, Ren X, Wu Z, Streeper RS, Bordone L (October 2010). "SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. In primary myotubes and hepatocytes, knockdown of SIRT4 results in increased Fatty Acid Oxidation, cellular respiration, and pAMPK levels. SIRT4 inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases associated with ectopic lipid storage such as type 2 diabetes". J. Biol. Chem. 285 (42): 31995–32002. doi:10.1074/jbc.M110.124164. PMC 2952200. PMID 20685656.
  9. ^ a b c d e Li S, Zheng W (2018). "Mammalian Sirtuins SIRT4 and SIRT7". Progress in Biophysics and Molecular Biology. Progress in Molecular Biology and Translational Science. 154: 147–168. doi:10.1016/bs.pmbts.2017.11.001. ISBN 9780128122617. PMID 29413176.
  10. ^ Yoo HC, Yu YC, Sung Y, Han JM (2020). "Glutamine reliance in cell metabolism". Experimental & Molecular Medicine. 52 (9): 1496–1516. doi:10.1038/s12276-020-00504-8. PMC 8080614. PMID 32943735.

Further reading[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.