Sirt5 Is an NAD-Dependent Protein Lysine Demalonylase and Desuccinylase

By Jintang Du, Yeyun Zhou, Xiaoyang Su, Jiujiu Yu, S. Khan, Hong Jiang, J. Kim, J. Woo, J. H. Kim, B. Choi and 7 more. Science, 2011

1,350 citations recorded by the source corpus.

Biological functions of sirtuins may involve lysine desuccinylase and demalonylase activities. Silent information regulator 2 (Sir2) proteins (sirtuins) are nicotinamide adenine dinucleotide–dependent deacetylases that regulate important biological processes. Mammals have seven sirtuins, Sirt1 to Sirt7. Four of them (Sirt4 to Sirt7) have no detectable or very weak deacetylase activity. We found that Sirt5 is an efficient protein lysine desuccinylase and demalonylase in vitro. The preference for succinyl and malonyl groups was explained by the presence of an arginine residue (Arg105) and tyrosine residue (Tyr102) in the acyl pocket of Sirt5. Several mammalian proteins were identified with mass spectrometry to have succinyl or malonyl lysine modifications. Deletion of Sirt5 in mice appeared to increase the level of succinylation on carbamoyl phosphate synthase 1, which is a known target of Sirt5. Thus, protein lysine succinylation may represent a posttranslational modification that can be reversed by Sirt5 in vivo.

Subfields: Epidemiology, Geriatrics and Gerontology, Oncology

View Paper: https://www.semanticscholar.org/paper/a06d9097ad61ef9b87b5b8098ed795796f4e18e3

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In Epidemiology

1. Kuo-Chen Chou
2. E. Seto

In Geriatrics and Gerontology

1. Ping Gao
2. Minoru Yoshida
3. E. Seto
4. Huafeng Zhang
5. Linchong Sun
6. M. Hirschey

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2. Kuo-Chen Chou
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8. Linchong Sun

Citations in the corpus

• NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, neutral): “(Du et al., 2011; Tan et al., 2014).”
• The Role of Sirtuins in Antioxidant and Redox Signaling (2017, background): “SIRT5 is also localized in the mitochondria, where it functions to deacetylate, demalonylate, and desuccinylate multiple proteins (38, 48).”
• SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks (2013, neutral): “SIRT5, a mitochondrial sirtuin with very weak deacetylase activity, is a potent desuccinylase (Du et al., 2011; Peng et al., 2011).”
• Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “There are variants on this theme: SIRT5 and SIRT6 have desuccinylation and defatty-acylation activities, respectively (Du et al., 2011; Jiang et al., 2013), while SIRT4 and SIRT6 can simply liberate NAM, leaving a covalently attached mono-ADP-ribose (Haigis et al., 2006; Liszt et al., 2005).”
• NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “SIRT5 is an NAD-dependent lysine desuccinylase, demalonylase, and deglutarylase.(228) BAT specific deletion of Sirt5 exhibits hypersuccinylation of proteins involved in the amino acid metabolism, ETC and FAO.”
• HAMAP in 2015: updates to the protein family classification and annotation system (2014, background): “Class III sirtuins, including the human SIR5 protein (UniProtKB/Swiss-Prot record Q9NXA8), were recently found to exhibit both protein demalonylase and protein desuccinylase activity (26,27).”
• Expert curation in UniProtKB: a case study on dealing with conflicting and erroneous data (2014, background): “A major breakthrough in the field came from two independent studies in late 2011 (10, 13).”
• pSuc-Lys: Predict lysine succinylation sites in proteins with PseAAC and ensemble random forest approach. (2016, background): “In histones, lysine succinylation is also present, suggesting that it possibly plays an important role in regulating chromatin structures and functions [5; 6].”