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Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5
Open accessAbstract
We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (Kglu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191 proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and increases our understanding of the deacylase SIRT5.
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“This work resulted in the identification of novel modifications targeted by SIRT5: succinylation, malonylation and glutarylation as described in details below ((Du et al. 2011{Zhang, 2011 #16);(Peng et al. 2011);(Tan et al. 2014)}.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“SIRT5 positively regulates CPS1 activity by mediating desuccinylation, deglutarylation and possibly by deacetylation across multiple sites ((Du et al. 2011))((Tan et al. 2014))((Nakagawa et al. 2009)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Mice lacking SIRT5 fail to upregulate CPS1 activity and show elevated blood ammonia under these conditions ((Nakagawa et al. 2009))((Tan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Moreover, HMGCS2 is also subject to glutarylation and malonylation ((Tan et al. 2014))((Nishida et al. 2015)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Interestingly, lysine 88 is also a target of succinylation and glutarylation ((Rardin, He, et al. 2013))((Tan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Both MnSOD and the various mitochondrial superoxide sources are acylated ((Rardin, Newman, et al. 2013), (Rardin, He, et al. 2013);(Tan et al. 2014)); MnSOD also carries glutarylation, succinylation, and acetylation at functionally required lysine residues near its active site, K122 in particular bears all three modifications ((Tao et al. 2010)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Mass-spectrometry data has shown that there are an abundance of histone crotonylation sites in all four core histones22,40.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [40]
In the citing paper
“For example, SIRT5 exhibits efficient activity to lysine desuccinylation, demalonylation and glutarylation12-14”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [14]
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Citations
Cites
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“Bioinformatic Analyses of Kglu Substrates To identify the possible association of Kglu substrates with cellular functions, we carried out gene ontology (GO) enrichment analysis using DAVID bioinformatics resources (Huang et al., 2009).”
MethodThe metabolic and molecular bases of inherited disease
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Self-citationAMPK: a nutrient and energy sensor that maintains energy homeostasis
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“In addition to histones, PTM-regulatory enzymes, such as AMP-activated protein kinase (AMPK) and lysine deacetylases (KDACs or HDACs), can control activity of their substrates (Chalkiadaki and Guarente, 2012; Hardie et al., 2012), many of which are metabolic enzymes.”
BackgroundTranscriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
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“For example, acetyl-CoA, SAM, NAD+, and a-ketoglutarate are donors/substrates or cofactors for histone lysine-modifying enzymes, i.e., those modulating levels of acetylation and methylation (Imai et al., 2000; Takahashi et al., 2006; Tsukada et al., 2006; Wellen et al., 2009).”
BackgroundInfluentialThe complex language of chromatin regulation during transcription
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“These PTM enzymes have important roles in modulation of chromatin structure and transcriptional regulation (Berger, 2007; Chi et al., 2010).”
BackgroundATP-citrate lyase links cellular metabolism to histone acetylation
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“For example, acetyl-CoA, SAM, NAD+, and a-ketoglutarate are donors/substrates or cofactors for histone lysine-modifying enzymes, i.e., those modulating levels of acetylation and methylation (Imai et al., 2000; Takahashi et al., 2006; Tsukada et al., 2006; Wellen et al., 2009).”
BackgroundHistone demethylation by a family of JmjC domain-containing proteins
Tsukada, Y.-I., Fang, J., Erdjument‐Bromage, H., Warren, M., Borchers, C. H., Tempst, P., & Zhang, Y. (2005) · Nature · doi:10.1038/nature04433 · Cited by 2,244 · cited 2×
“For example, acetyl-CoA, SAM, NAD+, and a-ketoglutarate are donors/substrates or cofactors for histone lysine-modifying enzymes, i.e., those modulating levels of acetylation and methylation (Imai et al., 2000; Takahashi et al., 2006; Tsukada et al., 2006; Wellen et al., 2009).”
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“Our previous studies identified new lysine acylation modifications on histones (Chen et al., 2007; Tan et al., 2011; Xie et al., 2012), including lysine crotonylation and succinylation, revealing potential crosstalk between cellular physiology and gene transcription.”
BackgroundSelf-citationProtein Structure Modeling with MODELLER
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Emerging Roles for SIRT5 in Metabolism and Cancer
Bringman, L. R., Guo, A. H., Lyssiotis, C. A., & Lombard, D. B. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7264 · Cited by 141
Self-citationSIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis
Greene, K. S., Lukey, M. J., Wang, X., Blank, B. S., Druso, J. E., Lin, M.-C. J., Stalnecker, C. A., Zhang, C., Abril, Y. L. N., Erickson, J. W., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1911954116 · Cited by 138
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SIRT 5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer
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“…several cellular metabolism pathways, including the TCA cycle and glycolysis (Nishida et al., 2015; Park et al., 2013), urea cycle (Nakagawa et al., 2009; Nakamura et al., 2012; Tan et al., 2014) and fatty acid oxidation (FAO; Colak et al., 2015; Rardin et al., 2013; Sadhukhan et al., 2016).”
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“Recently, three novel lysine PTMs were discovered and reported, including malonylation [6], succinylation [35, 36] and glutarylation [5], which share commonalities in terms of”
BackgroundThe emerging role of protein l-lactylation in metabolic regulation and cell signalling
Ren, H., Tang, Y., & Zhang, D. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01259-0 · Cited by 159
“Among the 18 known KDACs, some, such as class IIa HDACs, show limited activity towards acetylated substrates 55 ; others, such as SIRT5, selectively target negatively charged acyl groups, including malonyl, succinyl and glutaryl modifications 56–58 .”
YEATS Domain—A Histone Acylation Reader in Health and Disease
Zhao, D. Y., Li, Y., Xiong, X., Chen, Z., & Li, H. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.03.010 · Cited by 139
“HDAC3, Sirt1, Sirt2 and Sirt3 were reported to decrotonylate histones and Sirt5 was reported to have desuccinylation and deglutarylation activity [25, 30-32].”
Changes in the Acetylome and Succinylome of Bacillus subtilis in Response to Carbon Source
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Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease
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Seifert, T., Malo, M., Kokkola, T., Engen, K., Fridén‐Saxin, M., Wallén, E. A. A., Lahtela-Kakkonen, M. K., Jarho, E. M., & Luthman, K. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500930h · Cited by 125
Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3
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The Current State of NAD+‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets
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“There are also efforts put into deriving isotype-selective inhibitors of the “classical” KDACs, such as the KDAC6selective rocilinostat (6) (Fig.”
BackgroundThe lysine degradation pathway: Subcellular compartmentalization and enzyme deficiencies
Leandro, J., & Houten, S. M. (2020) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2020.07.010 · Cited by 122
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“At present, many types of histone PTMs have been identi fi ed, including acetylation [11], methylation [12], and newly discovered PTMs, such as succinylation [13], glutarylation [14], and crotonylation [15].”
Rovira‐Llopis, S., Apostolova, N., Bañuls, C., Muntané, J., Rocha, M., & Víctor, V. M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7313 · Cited by 125
“Sirtuin proteins are lysine deacetylases, with the exception of SIRT5, which is involved in other relevant activities, including demalonylation and desuccinylation of lysines (319).”
Chan, J. C., & Maze, I. S. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.05.009 · Cited by 126
“Under normal cellular conditions, the modified glutarate can be metabolized to glutaryl-coA, where transfer of this donor group metabolically labels proteins endogenously subjected to glutarylation [15].”
BackgroundInfluentialHDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine
Aramsangtienchai, P., Spiegelman, N. A., He, B., Miller, S. P., Dai, L., Zhao, Y., & Lin, H. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00396 · Cited by 118
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Why always lysine? The ongoing tale of one of the most modified amino acids
Azevedo, C., & Saiardi, A. (2015) · Advances in Biological Regulation · doi:10.1016/j.jbior.2015.09.008 · Cited by 119
Biochemical Genetic Pathways that Modulate Aging in Multiple Species: Figure 1.Preprint
Bitto, A., Wang, A. M., Bennett, C. F., & Kaeberlein, M. R. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025114 · Cited by 122
“Additionally, components of the pathway were subsequently identified in worms (Tissenbaum and Ruvkun 1998), and similar effects were reported for mutations that reduce IIS in flies (Clancy et al. 2001; Tatar et al. 2001; Tu et al. 2002).”
BackgroundPotential Modulation of Sirtuins by Oxidative Stress
Santos, L., Escande, C., & Denicola, A. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/9831825 · Cited by 120
Mossink, B., Negwer, M., Schubert, D., & Nadif Kasri, N. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03714-5 · Cited by 114
The roles of sirtuins family in cell metabolism during tumor development
Zhu, S., Dong, Z., Ke, X., Hou, J., Zhao, E., Zhang, K., Wang, F., Yang, L., Xiang, Z., & Cui, H. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.11.003 · Cited by 113
Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH
Madsen, A. S., Andersen, C. D., Daoud, M., Anderson, K. A., Laursen, J. S., Chakladar, S., Huynh, F. K., Colaço, A. R., Backos, D. S., Fristrup, P., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.668699 · Cited by 111
Self-citationMoniot, S., Forgione, M., Lucidi, A., Hailu, G. S., Nebbioso, A., Carafa, V., Baratta, F., Altucci, L., Giacchè, N., Passeri, D., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01609 · Cited by 110
Sun, X., Wang, S., Gai, J., Guan, J., Li, J., Li, Y., Zhao, J., Zhao, C., Fu, L., & Li, Q. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00754 · Cited by 112
“SIRT5 is a unique member of the Sirtuin family (Sirt1–7), which possesses multiple enzymatic activities including NAD-dependent histone deacetylase (1), potent lysine demalonylase, lysine desuccinylase (2), and lysine glutarylase (3) activities.”
BackgroundLiu, X., Sadhukhan, S., Sun, S., Wagner, G. R., Hirschey, M. D., Qi, L., Lin, H., & Locasale, J. W. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.044859 · Cited by 114
Self-citationHasan, M. M., Yang, S., Zhou, Y., & Mollah, M. N. H. (2015) · Molecular BioSystems · doi:10.1039/c5mb00853k · Cited by 109
Sirtuin 5 is required for mouse survival in response to cardiac pressure overload
Hershberger, K. A., Abraham, D., Martin, A. S., Mao, L., Liu, J., Gu, H., Locasale, J. W., & Hirschey, M. D. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.809897 · Cited by 105
“Aside from these targets, hundreds of sites of lysine succinylation (8), malonylation (11), and glutarylation (5) lack functional characterization.”
BackgroundSelf-citationThe Regulation and Function of Histone Crotonylation
Ntorla, A., & Burgoyne, J. R. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.624914 · Cited by 112
SIRT7 Is an RNA-Activated Protein Lysine Deacylase
Tong, Z., Wang, M., Wang, Y., Kim, D. D., Grenier, J. K., Cao, J., Sadhukhan, S., Hao, Q., & Lin, H. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00954 · Cited by 107
Progress in Nonalcoholic Fatty Liver Disease: SIRT Family Regulates Mitochondrial Biogenesis
Zeng, C., & Chen, M. (2022) · Biomolecules · doi:10.3390/biom12081079 · Cited by 108
“It not only has NAD+-dependent deacetylase activity, but also specifically removes succinyl, glutaryl, and malonic acid groups from lysine residues [52,99,165,166].”
BackgroundNatural Phytochemicals as SIRT Activators—Focus on Potential Biochemical Mechanisms
Wiciński, M., Erdmann, J., Nowacka, A., Kuźmiński, O., Michalak, K., Janowski, K., Ohla, J., Biernaciak, A., Szambelan, M., & Zabrzyński, J. (2023) · Nutrients · doi:10.3390/nu15163578 · Cited by 117
“SIRT1 and SIRT2 localize in the nucleus and cytoplasm; SIRT3, SIRT4 and SIRT5 are found in mitochondria; and SIRT6 and SIRT7 mostly reside in the nucleus and nucleoli [8,9].”
BackgroundInfluentialPannek, M., Simic, Z., Fuszard, M. A., Meleshin, M., Rotili, D., Mai, A., Schutkowski, M., & Steegborn, C. (2017) · Nature Communications · doi:10.1038/s41467-017-01701-2 · Cited by 103
Sirtuins' control of autophagy and mitophagy in cancer
Aventaggiato, M., Vernucci, E., Barreca, F., Russo, M. A., & Tafani, M. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107748 · Cited by 103
Chemical and structural biology of protein lysine deacetylases
Yoshida, M., Kudo, N., Kosono, S., & Ito, A. (2017) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.93.019 · Cited by 109
Huang, J. L., Luo, Z., Ying, W., Cao, Q., Huang, H., Dong, J., Wu, Q., Zhao, Y., Qian, X., & Dai, J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700796114 · Cited by 97
“In addition, several studies have demonstrated that Sirt5 (class III) is a de-succinylase, de-malonylase, and de-glutarylase both in vitro and in vivo (7, 11, 26).”
BackgroundSelf-citationTargeting sirtuins for cancer therapy: epigenetics modifications and beyond
Shen, H., Qi, X., Hu, Y., Wang, Y., Zhang, J., Liu, Z., & Qin, Z. (2024) · Theranostics · doi:10.7150/thno.100667 · Cited by 95
Fu, Y., Yu, J., Li, F., & Ge, S. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02338-w · Cited by 104
“Of particular interest, the core histone H2B has been revealed to have three Kglu sites (H2BK5, H2BK116, and H2BK120), which may be critical for chromatin-mediated processes, such as the regulation of gene expression [25].”
BackgroundInfluentialLysine succinylation, the metabolic bridge between cancer and immunity
Shen, R. D., Ruan, H., Lin, S., Liu, B., Song, H., Li, L., & Ma, T. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2022.10.028 · Cited by 100
“Studies have shown that there are arginine and tyrosine residues in the acyl bags of SIRT5,(16) so SIRT5 prefers short-chain carboxyl groups, such as malonyl and succinyl.(18) SIRT5 is a highly efficient protein lysine desuccinylase.”
BackgroundCircadian and Feeding Rhythms Orchestrate the Diurnal Liver Acetylome
Mauvoisin, D., Atger, F., Dayon, L., Galindo, A. N., Wang, J., Martín, E., Silva, L. D., Montoliu, I., Collino, S., Martin, F., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.065 · Cited by 94
“…for instance, has recently been shown to regulate glycolysis through reversible malonylation (Nishida et al., 2015), the urea cycle through deglutarylation (Tan et al., 2014), and ketogenesis as well as other metabolic pathways through desuccinylation (Park et al., 2013; Rardin et al., 2013a).”
Function and mechanism of histone β-hydroxybutyrylation in health and disease
Zhou, T., Cheng, X., He, Y., Xie, Y., Xu, F., Xu, Y., & Huang, W. G. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.981285 · Cited by 104
“Following the development of high-throughput and highsensitivity MS, until now, more than ten types of novel HPTMs, such as lysine propionylation (Kpr) (11), lysine butylation (Kbu) (11), lysine crotonylation (Kcr) (12), lysine malonylation (Kma) (13), lysine succinylation (Ksucc) (14), lysine glutarylation (Kglu) (15…”
BackgroundInfluentialPharmacological and genetic perturbation establish SIRT5 as a promising target in breast cancer
Abril, Y. L. N., Fernandez, I. R., Hong, J. Y., Chiang, Y., Kutateladze, D. A., Zhao, Q., Yang, M., Hu, J., Sadhukhan, S., Li, B., et al. (2021) · Oncogene · doi:10.1038/s41388-020-01637-w · Cited by 91
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“The reverse process occurs in the dark (Taiz et al., 2015; Buchanan, 2016).”
BackgroundThe CD38 glycohydrolase and the NAD sink: implications for pathological conditions
Zeidler, J. D., Hogan, K. A., Agorrody, G., Peclat, T., Kashyap, S., Kanamori, K. S., Gomez, L. S., Mazdeh, D. Z., Warner, G. M., Thompson, K. L., et al. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00451.2021 · Cited by 95
Epigenetic regulation in cancer therapy: From mechanisms to clinical advances
Tao, L., Zhou, Y., Luo, Y., Qiu, J., Xiao, Y., Zou, J., Zhang, Y., Liu, X., Yang, X., Gou, K., et al. (2024) · MedComm – Oncology · doi:10.1002/mog2.59 · Cited by 95
Self-citationMitochondrial Sirtuins in cardiometabolic diseases
Tang, X., Chen, X., Chen, H., & Liu, D. (2017) · Clinical Science · doi:10.1042/cs20160685 · Cited by 87
SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
Du, Y., Hu, H., Qu, S., Wang, J., Hua, C., Zhang, J., Wei, P., He, X., Hao, J., Liu, P., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.037 · Cited by 87
Bahl, S., & Seto, E. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03599-4 · Cited by 82
The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease
Batchu, S. N., Brijmohan, A. S., & Advani, A. (2016) · Clinical Science · doi:10.1042/cs20160084 · Cited by 86
Lysine acetylation in mitochondria: From inventory to function
Hosp, F., Lassowskat, I., Santoro, V., Vleesschauwer, D. D., Fliegner, D., Redestig, H., Mann, M., Christian, S., Hannah, M. A., & Finkemeier, I. (2016) · Mitochondrion · doi:10.1016/j.mito.2016.07.012 · Cited by 89
Papanicolaou, K. N., O'Rourke, B. P., & Foster, D. B. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00301 · Cited by 85
“Of note, Sirt5 exhibits broader specificity for modified lysines and in addition to desuccinylation, it can also perform demalonylation and deglutarylation (Du et al., 2011; Peng et al., 2011; Tan et al., 2014) (Figure 3).”
BackgroundWho watches the watchmen? Regulation of the expression and activity of sirtuins
Buler, M., Andersson, U., & Hakkola, J. (2016) · The FASEB Journal · doi:10.1096/fj.201600410rr · Cited by 92
Biochemistry and regulation of histone lysine l-lactylation
Sheng, X., Lin, H., Cole, P. A., & Zhao, Y. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00876-7 · Cited by 97
“Lys acylations, including but not limited to propionylation 194 , butyrylation 195 , malonylation 196 , succinylation 197,198 , β-hydroxybutyrylation 199 and glutarylation 189 , are also implicated in pathological conditions such as cancer, metabolic disorders, diabetes and immune dysfunction.”
Self-citationDiverse Activities of Histone Acylations Connect Metabolism to Chromatin Function
Dutta, A., Abmayr, S. M., & Workman, J. L. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.06.038 · Cited by 87
Gut, P., Matilainen, S., Meyer, J. G., Pällijeff, P., Richard, J., Carroll, C. J., Euro, L., Jackson, C. B., Isohanni, P., Minassian, B. A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19743-4 · Cited by 83
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Histone benzoylation serves as an epigenetic mark for DPF and YEATS family proteins
Ren, X., Zhou, Y., Xue, Z., Hao, N., Li, Y., Guo, X., Wang, D., Shi, X., & Li, H. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1130 · Cited by 83
“Up to date, over ten types of histone acylation have been identified, including formylation (Kfo) (4), propionylation (Kpr) and butyrylation (Kbu) (5), crotonylation (Kcr) (6), malonylation (Kma) and succinylation (Ksucc) (7), glutarylation (Kglu) (8), 2hydroxyisobutyrylation (Khib) (9), -hydroxybutyrylation (Kbhb) (1…”
BackgroundZhou, B., Yang, Y., Pang, X., Shi, J., Jiang, T., & Zheng, X. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115071 · Cited by 82
The TRIM33 Bromodomain Recognizes Histone Lysine Lactylation
Nuñez, R., Sidlowski, P. F. W., Steen, E. A., Wynia‐Smith, S. L., Sprague, D. J., Keyes, R. F., & Smith, B. C. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00248 · Cited by 92
Zwaans, B. M. M., & Lombard, D. B. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.016287 · Cited by 81
“Some sirtuins remove noncanonical lysine post-translational modifications such as succinyl, malonyl, glutaryl and acyl groups (Du et al., 2011; Feldman et al., 2013; Jiang et al., 2013; Peng et al., 2011; Tan et al., 2014).”
BackgroundSelf-citationSubcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies
Zhu, Y., Liu, J., Park, J., Rai, P., & Zhai, R. G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.04.002 · Cited by 82
“SIRT5 is an inefficient deacetylase; instead it regulates its target protein activity by NAD+-dependent removal of malonyl, glutaryl, or succinyl groups from lysine residues (Du et al., 2011; Tan et al., 2014).”
BackgroundSelf-citationQian, L., Nie, L., Chen, M., Liu, P., Zhu, J., Zhai, L., Tao, S., Cheng, Z., Zhao, Y., & Tan, M. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.6b00264 · Cited by 81
Self-citationBetsinger, C. N., & Cristea, I. M. (2019) · Journal of Proteome Research · doi:10.1021/acs.jproteome.9b00086 · Cited by 84
Protein lysine de-2-hydroxyisobutyrylation by CobB in prokaryotes
Dong, H., Zhai, G., Chen, C., Bai, X. F., Tian, S., Hu, D., Fan, E., & Zhang, K. (2019) · Science Advances · doi:10.1126/sciadv.aaw6703 · Cited by 81
NAD Biosynthesis in Humans - Enzymes, Metabolites and Therapeutic Aspects
Dölle, C., Skoge, R. H., VanLinden, M. R., & Ziegler, M. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/15680266113136660206 · Cited by 80
de Cima, S., Polo, L. M., Díez‐Fernández, C., Martínez, A. I. E., Cervera, J., Fita, I., & Rubio, V. (2015) · Scientific Reports · doi:10.1038/srep16950 · Cited by 79
The Expanding Constellation of Histone Post-Translational Modifications in the Epigenetic Landscape
Cavalieri, V. (2021) · Genes · doi:10.3390/genes12101596 · Cited by 87
An Expanding Repertoire of Protein Acylations
Xu, Y., Shi, Z., & Bao, L. (2022) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2022.100193 · Cited by 80
“In recent years, researchers found that p300-mediated Khib could also regulate glycolysis (38).”
BackgroundInfluentialTao, J., Zhang, J., Ling, Y., McCall, C. E., & Liu, T. F. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00419 · Cited by 77
Chromatin as a key consumer in the metabolite economy
Diehl, K. L., & Muir, T. W. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0517-x · Cited by 82
Zeng, Q.-M., Wang, K., Zhao, Y., Ma, Q., Chen, Z., & Huang, W. (2023) · Biomolecules · doi:10.3390/biom13030417 · Cited by 79
“The types of posttranslational protein modifications include oxidative modification [35], phosphorylation [36], ubiquitination [37], methylation [38], formylation [39], acetylation [40], propionylation [41], malonylation [42], butyrylation [43], glutarylation [44], succinylation [45], crotonylation [46], and lactylati…”
BackgroundSelf-citationSirtuin family in autoimmune diseases
Tao, Z., Jin, Z., Wu, J., Cai, G., & Yu, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1186231 · Cited by 79
“SIRT5 exhibits enzyme activity mediated by speci fi c Arg for malonylation, succinylation, and glutarylation (21, 22).”
Rajabi, N., Auth, M., Troelsen, K. R., Pannek, M., Bhatt, D. P., Fontenas, M., Hirschey, M. D., Steegborn, C., Madsen, A. S., & Olsen, C. A. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201709050 · Cited by 76
Self-citationThe Aging Metabolome—Biomarkers to Hub Metabolites
Sharma, R. B., & Ramanathan, A. (2020) · PROTEOMICS · doi:10.1002/pmic.201800407 · Cited by 81
Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors
Yang, L., Ma, X., He, Y., Chen, Y., Chen, Q., Li, G., & Chen, X. (2016) · Science China Life Sciences · doi:10.1007/s11427-016-0060-7 · Cited by 76
“SIRT5 has become an active topic of research towards its biological and physiological functions (Du et al., 2011; Nishida et al., 2015; Polletta et al., 2015; Tan et al., 2014).”
BackgroundSelf-citationJu, Z., & He, J. (2017) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2017.07.022 · Cited by 74
Mitochondrial Sirtuins in Reproduction
Emidio, G. D., Falone, S., Artini, P. G., Amicarelli, F., D’Alessandro, A. M., & Tatone, C. (2021) · Antioxidants · doi:10.3390/antiox10071047 · Cited by 74
“Later, other researchers found in SIRT5 knock-out mice hundreds of proteins with highly malonylated and glutarylated lysines [84,85].”
BackgroundSirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability
Wang, H.-L., Chen, Y., Wang, Y.-Q., Tan, J., Tan, J., Liu, Q., Li, C.-M., Tong, X., Gao, Q., Hong, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33903-8 · Cited by 78
Self-citationHistone Acylation beyond Acetylation: Terra Incognita in Chromatin Biology.
Rousseaux, S., & Khochbin, S. (2015) · PubMed · doi:10.22074/cellj.2015.506 · Cited by 74
“probably catalyse the establishment of additional acyl groups such as succinyl and glutaryl (6).”
InfluentialThe Role of Sirtuins in Kidney Diseases
Hong, Y. A., Kim, J. E., Jo, M.-J., & Ko, G.-J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186686 · Cited by 74
“The absence of SIRT5 led to hypersuccinylation of mitochondrial proteins in the kidney [62,63] and increased blood ammonia levels [64], suggesting that SIRT5 may play roles in renal and liver metabolism.”
BackgroundA global view of the human post-translational modification landscape
Kitamura, N., & Galligan, J. J. (2023) · Biochemical Journal · doi:10.1042/bcj20220251 · Cited by 81
SIRT2 Reverses 4-Oxononanoyl Lysine Modification on Histones
Jin, J., He, B., Zhang, X., Lin, H., & Wang, Y. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b04977 · Cited by 73
Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., Zhang, J., et al. (2019) · PLOS ONE · doi:10.1371/journal.pone.0211796 · Cited by 72
Self-citationHistone succinylation and its function on the nucleosome
Liu, J., Shangguan, Y., Tang, D., & Dai, Y. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16676 · Cited by 87
Liu, X., Zhu, C., Zha, H., Tang, J., Rong, F., Chen, X., Fan, S., Xu, C., Du, J., Zhu, J., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019103285 · Cited by 74
“However, in addition to desuccinylase activity, demalony-lase, and deglutarylase activity have been revealed for SIRT5 (Du et al , 2011; Tan et al , 2014; Nishida et al , 2015).”
Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection
Fabbrizi, E., Fiorentino, F., Carafa, V., Altucci, L., Mai, A., & Rotili, D. (2023) · Cells · doi:10.3390/cells12060852 · Cited by 77
“Carbamoyl phosphate synthetase 1 (CPS1), an enzyme involved in the conversion of ammonia and bicarbonate into carbamoyl phosphate, is deacylated and activated by SIRT5 in liver cells [52,68,86,87].”
BackgroundUsing mitochondrial sirtuins as drug targets: disease implications and available compounds
Gertz, M., & Steegborn, C. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2180-7 · Cited by 73
“deacylation activity against malonyl, succinyl, and glutaryl modifications of protein Lys residues [44, 151, 165, 166].”
BackgroundKeeping the balance in NAD metabolism
Strømland, Ø., Niere, M., Nikiforov, A. A., VanLinden, M. R., Heiland, I., & Ziegler, M. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180417 · Cited by 73
Extranuclear Sirtuins and Metabolic Stress
Elkhwanky, M., & Hakkola, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7270 · Cited by 67
Accelerating the Field of Epigenetic Histone Modification Through Mass Spectrometry–Based Approaches
Lu, C., Coradin, M., Porter, E. G. P., & Garcia, B. A. (2020) · Molecular & Cellular Proteomics · doi:10.1074/mcp.r120.002257 · Cited by 71
Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5
Fiorentino, F., Castiello, C., Mai, A., & Rotili, D. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00687 · Cited by 70
Costa‐Machado, L. F., & Fernández-Marcos, P. J. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1634953 · Cited by 66
“SIRT5, another mitochondrial sirtuin with 310 amino acids in humans, removes acyl groups (succinate, malonate, and glutarate) from lysine residues in different mitochondrial enzymes [177,178].”
BackgroundSIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia
Yan, D., Franzini, A., Pomicter, A. D., Halverson, B. J., Antelope, O., Mason, C. C., Ahmann, J. M., Senina, A. V., Vellore, N. A., Jones, C. L., et al. (2021) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-20-0168 · Cited by 66
“While SIRT3 has been shown to positively regulate SOD2 by lysine deacetylation (61), there is no evidence that deacylation of any SOD2 lysines is controlled by SIRT5 (34, 35, 37, 38).”
BackgroundSelf-citationAccelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension
Rinschen, M. M., Palygin, O., El‐Meanawy, A., Domingo-Almenara, X., Palermo, A., Dissanayake, L. V., Golosova, D., Schafroth, M. A., Guijas, C., Demir, F., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31670-0 · Cited by 65
The Role of SIRT3 in the Brain Under Physiological and Pathological Conditions
Sidorova‐Darmos, E., Sommer, R., & Eubanks, J. H. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00196 · Cited by 66
“SIRT1 Deacetylase (Michishita et al., 2005), Decrotonylase (Bao et al., 2014) SIRT2 Deacetylase (Perrod et al., 2001; North et al., 2003), Decrotonylase (Bao et al., 2014) SIRT3 Deacetylase (Schwer et al., 2002), Decrotonylase (Bao et al., 2014) SIRT4 ADP-ribosyltransferase (Ahuja et al., 2007), Lipoamidase (Mathias e…”
SIRT4 and Its Roles in Energy and Redox Metabolism in Health, Disease and During Exercise
Han, Y., Zhou, S., Coetzee, S., & Chen, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01006 · Cited by 72
Metadata
- Authors
- Tan, M., Peng, C., Anderson, K. A., Chhoy, P., Xie, Z., Dai, L., Park, J., Chen, Y., Huang, H., Zhang, Y., Ro, J., Wagner, G. R., Green, M. F., Madsen, A. S., Schmiesing, J., Peterson, B. S., Xu, G., Ilkayeva, O. R., Muehlbauer, M. J., Braulke, T., Mühlhausen, C., Backos, D. S., Olsen, C. A., McGuire, P. J., Pletcher, S. D., Lombard, D. B., Hirschey, M. D., & Zhao, Y.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of Chicago (US)
- Duke University (US)
- University of Michigan (US)
- Technical University of Denmark (DK)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Colorado Anschutz (US)
- National Institutes of Health (US)
- Corresponding author
- Hirschey, Matthew D.
- Zhao, Yingming
- ORCID
- Tan, Minjia
- Peng, Chao
- Chhoy, Peter
- Xie, Zhongyu
- Dai, Lunzhi
- Huang, He
- Zhang, Yi
- Ro, Jennifer
- Green, Michelle F.
- Madsen, Andreas S.
- Xu, Guofeng
- Ilkayeva, Olga R.
- Muehlbauer, Michael J.
- Braulke, Thomas
- Mühlhausen, Chris
- Backos, Donald S.
- Olsen, Christian A.
- McGuire, Peter J.
- Pletcher, Scott D.
- Lombard, David B.
- Hirschey, Matthew D.
- Zhao, Yingming
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 19
- Issue
- 4
- Pages
- 605-617
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4108075
- OpenAlex
- W2088511656
- Cited by
- 844
- References
- 45
- Citations by year
- 2026: 49 · 2025: 63 · 2024: 86 · 2023: 50 · 2022: 79 · 2021: 106 · 2020: 67 · 2019: 74 · 2018: 80 · 2017: 53 · 2016: 70 · 2015: 50 · 2014: 16
- FWCI
- 32.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion)
- Funders
- Lundbeckfonden (R52-2010-5054)
- National Institutes of Health (UL1TR000430)
- National Institute on Alcohol Abuse and Alcoholism (AA022146, R01AA022146)
- National Institute on Aging (F31AG047696, R01AG045351, AG045351, P30AG013283, T32AG000114)
- National Cancer Institute (R21CA177925, CA160036, CA059365-19, U24CA160036, T32CA059365, CA177925)
- National Institute of General Medical Sciences (GM105933, T32GM007105, GM101171, T32GM007315, R01GM101171, R01GM105933)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK096493, P30DK020572)
- National Center for Research Resources (RR020839, U54RR020839)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- SIRT5, protein posttranslational modification, urea cycle, glutaric aciduria type I, glutaryl-CoA, mitochondrial proteins, metabolic enzymes
- MeSH terms
- Acyl Coenzyme A, Animals, Carbamoyl-Phosphate Synthase (Ammonia), Lysine, Models, Biological, Protein Processing, Post-Translational, Mass Spectrometry, Immunoblotting, Molecular Structure, Sirtuins, Proteomics, Mice
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