| Structural highlights
Function
SIR5_HUMAN NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins. Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting. Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro.[1] [2] [3] [4]
Publication Abstract from PubMed
SIRT5, one of the mammalian sirtuins, specifically recognizes succinyl-lysine residues on proteins and catalyzes the desuccinylation reaction. In this study, we characterized SIRT5 mutants with hydrophobic amino acid substitutions at Q140 and N141, in addition to the catalytic residue H158, known as an active site residue, by the Michaelis-Menten analysis and X-ray crystallography. Kinetic analysis showed that the catalytic efficiency (k(cat)/K(m)) of the Q140L and N141V mutants decreased to 0.02 times and 0.0038 times that of the wild-type SIRT5, respectively, with the activity of the N141V mutant becoming comparable to that of the H158M mutant. Our findings indicate that N141 contributes significantly to the desuccinylation reaction.
SIRT5 mutants reveal the role of conserved asparagine and glutamine residues in the NAD(+)-binding pocket.,Yokoyama T, Takayama Y, Mizuguchi M, Nabeshima Y, Kusaka K FEBS Lett. 2024 Sep;598(18):2269-2280. doi: 10.1002/1873-3468.14961. Epub 2024 , Jun 20. PMID:39031546[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. 2008 Oct 10;382(3):790-801. doi: 10.1016/j.jmb.2008.07.048. Epub 2008, Jul 25. PMID:18680753 doi:10.1016/j.jmb.2008.07.048
- ↑ Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, Luo H, Zhang Y, He W, Yang K, Zwaans BM, Tishkoff D, Ho L, Lombard D, He TC, Dai J, Verdin E, Ye Y, Zhao Y. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics. 2011 Dec;10(12):M111.012658. doi: 10.1074/mcp.M111.012658., Epub 2011 Sep 9. PMID:21908771 doi:http://dx.doi.org/10.1074/mcp.M111.012658
- ↑ Lin ZF, Xu HB, Wang JY, Lin Q, Ruan Z, Liu FB, Jin W, Huang HH, Chen X. SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem Biophys Res Commun. 2013 Nov 8;441(1):191-5. doi:, 10.1016/j.bbrc.2013.10.033. Epub 2013 Oct 16. PMID:24140062 doi:http://dx.doi.org/10.1016/j.bbrc.2013.10.033
- ↑ 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. 2011 Nov 11;334(6057):806-9. PMID:22076378 doi:10.1126/science.1207861
- ↑ Yokoyama T, Takayama Y, Mizuguchi M, Nabeshima Y, Kusaka K. SIRT5 mutants reveal the role of conserved asparagine and glutamine residues in the NAD(+)-binding pocket. FEBS Lett. 2024 Sep;598(18):2269-2280. PMID:39031546 doi:10.1002/1873-3468.14961
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