Sirtuin 5 Explained

Sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae), also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.^[1]

This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and belong to the class III of the [histone deacetylase] superfamily, and are dependent on NAD+ as co-factor of enzymatic activities. SIRT5 is one of the three sirtuins localized primarily to the mitochondrion.

Structure

Alternative splicing of this gene results in two transcript variants. The protein structure of SIRT5 has been resolved and shows high degrees of structural conservation with other sirtuins, such as the ancestral yeast protein and human SIRT2.

Function

SIRT5 has been found to exhibit enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing acetyl, succinyl, and malonyl groups from the lysine residues of proteins.^[2] SIRT5 deacetylases and regulates carbamoyl phosphate synthetase (CPS1), the rate-limiting and initiating step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity. Mice with deletion of SIRT5 show elevated ammonia levels after a prolonged fast, whereas in contrast, mice overexpressing SIRT5 show increased CPS1 activity, suggesting one of the functions of SIRT5 may be to regulate the urea cycle.^[3] SIRT5 also interacts with and deacetylates cytochrome c.^[4] Large-scale profiling studies of SIRT5 deacetylase activity have uncovered over 700 protein substrates, including proteins localized to the mitochondria, the cytosol and other sub cellular localization. The identities of SIRT5 desuccinylation substrates suggest that SIRT5-mediated desuccinylation may be involved in energy metabolism.^[5]

The physiological consequences of SIRT5 molecular functions in human is under investigation but may involved regulations of mitochondrial metabolism.^[6]

Interactions

NAD+

Cytochrome c^[4]

Carbamoyl phosphate synthetase (CPS1)

Further reading

• Frye RA . 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 . Biochemical and Biophysical Research Communications . 260 . 1 . 273–79 . Jun 1999 . 10381378 . 10.1006/bbrc.1999.0897 .
• Frye RA . Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins . Biochemical and Biophysical Research Communications . 273 . 2 . 793–98 . Jul 2000 . 10873683 . 10.1006/bbrc.2000.3000 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . Nov 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . Oct 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–18 . Jan 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Mahlknecht U, Ho AD, Letzel S, Voelter-Mahlknecht S . Assignment of the NAD-dependent deacetylase sirtuin 5 gene (SIRT5) to human chromosome band 6p23 by in situ hybridization . Cytogenetic and Genome Research . 112 . 3–4 . 208–12 . 2006 . 16484774 . 10.1159/000089872 . 39811255 .
• Chowdari KV, Northup A, Pless L, Wood J, Joo YH, Mirnics K, Lewis DA, Levitt PR, Bacanu SA, Nimgaonkar VL . DNA pooling: a comprehensive, multi-stage association analysis of ACSL6 and SIRT5 polymorphisms in schizophrenia . Genes, Brain and Behavior . 6 . 3 . 229–39 . Apr 2007 . 16827919 . 10.1111/j.1601-183X.2006.00251.x . 44288193 . free .

Notes and References

1. Web site: Entrez Gene: SIRT5 sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae).
2. Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, He B, Chen W, Zhang S, Cerione RA, Auwerx J, Hao Q, Lin H . Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase . Science . 334 . 6057 . 806–09 . 2011 . 22076378 . 3217313 . 10.1126/science.1207861 . 2011Sci...334..806D .
3. Nakagawa T, Lomb DJ, Haigis MC, Guarente L . SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle . Cell . 137 . 3 . 560–70 . 2009 . 19410549 . 2698666 . 10.1016/j.cell.2009.02.026 .
4. Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C . Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5 . J. Mol. Biol. . 382 . 3 . 790–801 . 2008 . 18680753 . 10.1016/j.jmb.2008.07.048 .
5. Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, Xie Z, Zhang Y, Zwaans BM, Skinner ME, Lombard DB, Zhao Y . SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways . Mol. Cell . 50 . 6 . 919–30 . 2013 . 23806337 . 3769971 . 10.1016/j.molcel.2013.06.001 .
6. Verdin E, Hirschey MD, Finley LW, Haigis MC . Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling . Trends Biochem. Sci. . 35 . 12 . 669–75 . 2010 . 20863707 . 2992946 . 10.1016/j.tibs.2010.07.003 .