| 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
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more "drug-like" properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for sirtuins. This is important information when applying inhibitors to probe mechanisms in biology.
Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.,Rajabi N, Auth M, Troelsen KR, Pannek M, Bhatt D, Fontenas M, Hirshey MD, Steegborn C, Madsen AS, Olsen CA Angew Chem Int Ed Engl. 2017 Oct 17. doi: 10.1002/anie.201709050. PMID:29044784[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
- ↑ Rajabi N, Auth M, Troelsen KR, Pannek M, Bhatt D, Fontenas M, Hirshey MD, Steegborn C, Madsen AS, Olsen CA. Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. Angew Chem Int Ed Engl. 2017 Oct 17. doi: 10.1002/anie.201709050. PMID:29044784 doi:http://dx.doi.org/10.1002/anie.201709050
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