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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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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).”
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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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“coli and HeLa cells, we used an affinity enrichment-based proteomics approach as previously described (Chen et al., 2012; Kim et al., 2006).”
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Metabolic Effects of Caloric Restriction
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“SIRT5 removes malonyl and succinyl 4-carbon groups (Du et al. , 2011) and 5-carbon glutaryl groups (Tan et al. , 2014) as opposed to the shorter acetyl group.”
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“The enzymatic activities of CddA, A0319, A2827, A1994, and A1628 were measured as previously described (Peng et al., 2011; Tan et al., 2014) with slight modifications.”
Continuous Fluorescent Sirtuin Activity Assay Based on Fatty Acylated Lysines
Zessin, M., Meleshin, M., Hilscher, S., Schiene‐Fischer, C., Bařinka, C., Jung, M., & Schutkowski, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087416 · Cited by 14
“Additionally, F4 proved to be a surprisingly good substrate for SIRT5, which is known to be specific for negatively charged acyl residues such as malonyl [62], succinyl [23], and glutaryl [63] residues.”
BackgroundNicotinamide riboside activates SIRT5 deacetylation
Curry, A. M., Rymarchyk, S., Herrington, N. B., Donu, D., Kellogg, G. E., & Cen, Y. (2023) · FEBS Journal · doi:10.1111/febs.16887 · Cited by 14
Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity
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A Molecular Perspective and Role of NAD+ in Ovarian Aging
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“SIRT-5: SIRT5, the third mitochondrial sirtuin, possesses deglutarylase, desuccinylase, and demalonylase activities [117,118].”
BackgroundSun, L., Meng, H., Liu, T., Zhao, Q., Xia, M., Zhao, Z., Qian, Y., Hao, C., Zhong, X., Chai, K., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107785 · Cited by 14
“In recent years, several new types of short-chain fatty acyl-ations have been identi fi ed, including malonylation, propio-nylation, butyrylation, succinylation, glutarylation, lactylation and some others (7, 24, 25).”
BackgroundMitonuclear Communication in Stem Cell Function
Peng, B., Wang, Y., & Zhang, H. (2024) · Cell Proliferation · doi:10.1111/cpr.13796 · Cited by 14
“SIRT5 is crucial for modulating various post-translational modifications of lysine, such as acetylation, malonylation, glutarylation and succinylation [232–235].”
Todisco, S., Iacobazzi, D., Santarsiero, A., Convertini, P., & Infantino, V. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102233 · Cited by 15
“Tan et al. re-ported that lysine glutarylation is regulated by deacetylase, sirtuin 5 [135].”
Quantitative Analysis of the Sirt5-Regulated Lysine Succinylation Proteome in Mammalian Cells
Chen, Y. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3524-6_2 · Cited by 14
Self-citationComputational Identification of Lysine Glutarylation Sites Using Positive- Unlabeled Learning
Ju, Z., & Wang, S. (2020) · Current Genomics · doi:10.2174/1389202921666200511072327 · Cited by 13
Jia, J., Sun, M., Wu, G., & Qiu, W. (2022) · Mathematical Biosciences & Engineering · doi:10.3934/mbe.2023132 · Cited by 14
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Biochemical Analysis of Histone Succinylation
Yokoyama, A., Katsura, S., & Sugawara, A. (2017) · Biochemistry Research International · doi:10.1155/2017/8529404 · Cited by 15
“However, there are reports that p300 has histone succinylation activity in vitro [17, 30, 31].”
BackgroundThe Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy
Zavileyskiy, L. G., Aleshin, V. A., Kaehne, T., Karlina, I. S., Artiukhov, A. V., Maslova, M. V., Graf, A. V., & Bunik, V. I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012302 · Cited by 13
“While the roles of mitochondrial acyl transferases are under debate [23,38,58], in cytosol and the nucleus, enzymatic acylation prevails and regulates almost all glycolytic enzymes [58].”
BackgroundMultifunctional activity-based chemical probes for sirtuins
Sharma, C., Donu, D., Curry, A. M., Barton, E. E., & Cen, Y. (2023) · RSC Advances · doi:10.1039/d3ra02133e · Cited by 13
Liu, Y., Mei, G., Yang, Y., Cui, J., Peng, S., Peng, Z., & Cheng, Y. (2023) · Food and Chemical Toxicology · doi:10.1016/j.fct.2023.113991 · Cited by 13
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Current computational tools for protein lysine acylation site prediction
Qin, Z., Ren, H., Zhao, P., Wang, K., Liu, H., Miao, C., Du, Y., Li, J., Wu, L., & Chen, Z. (2024) · Briefings in Bioinformatics · doi:10.1093/bib/bbae469 · Cited by 13
The Structures, Functions, and Roles of Class III HDACs (Sirtuins) in Neuropsychiatric Diseases
Bonomi, R. E., Riordan, W., & Gelovani, J. G. (2024) · Cells · doi:10.3390/cells13191644 · Cited by 14
“Literature reports have suggested that SIRT5 is the only sirtuin with the ability to act as a deglutarylase [134].”
BackgroundRajabi, 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 · doi:10.1002/ange.201709050 · Cited by 14
Self-citationCiarlo, E., & Roger, T. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3667-0_21 · Cited by 13
Metabolic pathways at the crossroads of diabetes and inborn errors
Goetzman, E. S., Gong, Z., Schiff, M., Wang, Y., & Muzumdar, R. H. (2017) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-017-0091-x · Cited by 16
“Glutaryl-CoA dehydrogenase (GCDH) knockout mice have increased glutaryl-CoA and elevated lysine glutarylation (Tan et al 2014).”
Wang, M., Zhu, R., Small, D., Lin, L., Li, L., Ma, S., Xia, L., Luo, S., He, W., Yu, J., et al. (2025) · Leukemia · doi:10.1038/s41375-025-02673-9 · Cited by 15
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Self-citationBons, J., Rose, J., Zhang, R., Burton, J. B., Carrico, C., Verdin, E. M., & Schilling, B. (2022) · PROTEOMICS · doi:10.1002/pmic.202100371 · Cited by 13
“SIRT5 presents high levels of enzymatic activities, such as desuccinylase [11, 12, 24], demalonylase [11, 12, 26, 27], and deglutarylase [28], but low acetylase activity [29].”
Impact of Lysine Succinylation on the Biology of Fungi
Adejor, J., Tumukunde, E., Li, G., Lin, H., Xie, R., & Wang, S. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46020065 · Cited by 12
“Presently, in mammals, researchers have identified over ten distinct forms of lysine acylation, which include malonylation [32], succinylation [25], glutarylation [60], crotonylation [61], propionylation, butyrylation [62], 2-hydroxyisobutyrylation [63,64] and lactylation [65], among others.”
BackgroundResearch advances on epigenetics and cancer metabolism
Han, H., Feng, F., & Li, H. (2021) · Journal of Zhejiang University (Medical Sciences) · doi:10.3724/zdxbyxb-2021-0053 · Cited by 12
“[82] TAN M, PENG C, ANDERSON K A, et al.”
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Novel post-translational modifications in the kidneys for human health and diseases
Xiang, T., Zhao, S., Wu, Y., Li, L., Fu, P., & Ma, L. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121188 · Cited by 13
Generation and Purification of Catalytically Active Recombinant Sirtuin5 (SIRT5) Protein
Kumar, S., & Lombard, D. B. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3667-0_16 · Cited by 11
“mediated modification of carbamoyl phosphate synthetase 1 (CPS1) (15,10,13), 3hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) (12), Cu/Zn superoxide dismutase (SOD1) (16) and urate oxidase (17) increases enzymatic activity, while desuccinylation of pyruvate dehydrogenase complex (PDC) and succinate dehydrogenase (SDH…”
Self-citationChakraborty, J., Nemeria, N. S., Farinas, E. T., & Jordan, F. (2018) · FEBS Open Bio · doi:10.1002/2211-5463.12431 · Cited by 12
Green, S. R., & Storey, K. B. (2018) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-018-3468-8 · Cited by 12
Central Metabolism in Mammals and Plants as a Hub for Controlling Cell Fate
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“By depending on NAD, sirtuins are strictly coupled to the NAD/ NADH redox state and the energy status of the cell and can respond to any imbalances imposed upon the cell and requiring adjustment of energy metabolism (133, 181, 201).”
BackgroundSirtuins, Healthspan, and Longevity in Mammals
Giblin, W., & Lombard, D. B. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-411596-5.00003-4 · Cited by 12
Self-citationSirtuin activation as a therapeutic approach against inborn errors of metabolism
Bleeker, J. C., & Houtkooper, R. H. (2016) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-016-9939-8 · Cited by 11
“…non-histone proteins in different compartments of the cell and members of the p300/CREB family of KATs have been shown to catalyze propionylation, butyrylation, crotonylation and succinylation as well (Chen et al 2007; Cheng et al 2009; Tan et al 2014; Hirschey and Zhao 2015; Sabari et al 2015).”
InfluentialSuccinylation – encoded metabolic codes: cracking the molecular logic of cellular adaptation
Cong, Y., Zhang, X., Wang, Z., Cui, Z., Li, C., Han, Y., Deng, W., Zhou, X., Wu, H., Sun, J., et al. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000003249 · Cited by 11
“The enzymatic activity of PKM2 was shown to be regulated by succinylation [143] .”
Molecular Basis of KAT2A Selecting Acyl-CoA Cofactors for Histone Modifications
Li, S., Li, N., He, J., Zhou, R., Lu, Z., Tao, Y. J., Guo, Y. R., & Wang, Y. (2023) · Research · doi:10.34133/research.0109 · Cited by 13
“Lysine acylation is a group of lysine modifications chemically related to acetylation, including propionylation [1], butyrylation [1], malonylation [2], succinylation [2], glutarylation [3], crotonylation [4], and 2-hydroxyisobutyrylation [5].”
BackgroundHuang, T., Xu, X., Chen, S., Liu, Z., Huang, Y., Huo, X., & Chen, G. (2025) · Environment International · doi:10.1016/j.envint.2025.109549 · Cited by 11
Sirtuin 5 Is Regulated by the SCF Cyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control
Mills, C. A., Wang, X., Bhatt, D. P., Grimsrud, P. A., Matson, J. P., Lahiri, D., Burke, D. J., Cook, J. G., Hirschey, M. D., & Emanuele, M. J. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00269-20 · Cited by 11
Self-citationExtending the HSA-Cys34-Adductomics Pipeline to Modifications at Lys525
Grigoryan, H., Imani, P., Dudoit, S., & Rappaport, S. M. (2021) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.1c00311 · Cited by 12
Muroski, J. M., Fu, J. Y., Nguyen, H. H., Wofford, N. Q., Mouttaki, H., James, K. L., McInerney, M. J., Gunsalus, R. P., Loo, J. A., & Loo, R. R. O. (2022) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2022.100215 · Cited by 11
“Interestingly, the sirtuin assayed in this system appears to have a bias for longer chain acylations, particularly glutarylation, a trait that is shared with Sirt4 and Sirt5 in mammalian systems (66, 85, 86).”
BackgroundDehomocysteinylation is catalysed by the sirtuin‐2‐like bacterial lysine deacetylase CobB
Mei, X., He, X., Huang, L., Qi, D., Nie, J., Li, Y., Si, W., & Zhao, S. (2016) · FEBS Journal · doi:10.1111/febs.13912 · Cited by 12
Rooker, D. R., Klyubka, Y., Gautam, R., Tomat, E., & Buccella, D. (2017) · ChemBioChem · doi:10.1002/cbic.201700582 · Cited by 11
Protein hypoacylation induced by Sirt5 overexpression has minimal metabolic effect in mice
Bentley, N. L., Fiveash, C. E., Osborne, B., Quek, L., Ogura, M., Inagaki, N., Cooney, G. J., Polly, P., Montgomery, M. K., & Turner, N. A. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.07.047 · Cited by 11
Unveiling the role of GAS41 in cancer progression
Ji, K., Li, L., Liu, H., Shen, Y., Jiang, J. D., Zhang, M., Teng, H., Yan, X., Zhang, Y., Cai, Y., et al. (2023) · Cancer Cell International · doi:10.1186/s12935-023-03098-z · Cited by 10
“5C), exhibits diverse functions in eukaryotic cells [136–139].”
BackgroundSelf-citationVahid, Z. F., Eskandani, M., Dadashi, H., Vandghanooni, S., & Rashidi, M. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e40756 · Cited by 14
Zhang, L., Lv, T., Hou, P.-P., Jin, Y., & Jia, F. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149613 · Cited by 12
DNAzymes for amine and peptide lysine acylation
Yao, T., Przybyla, J. J., Yeh, P., Woodard, A. M., Nilsson, H. J., Brandsen, B. M., & Silverman, S. K. (2020) · Organic & Biomolecular Chemistry · doi:10.1039/d0ob02015j · Cited by 11
Proteome-Wide Analysis of Lysine 2-Hydroxyisobutyrylated Proteins in Fusarium oxysporum
Qian, H., Wang, L., Ma, X.-L., Yi, X., Wang, B., & Liang, W. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.623735 · Cited by 10
“…(Kglu), which were named lysine acylation (Chen et al., 2007; Frontiers in Microbiology | www.frontiersin.org 1 February 2021 | Volume 12 | Article 623735 Peng et al., 2011; Peach et al., 2012; Tan et al., 2014; Li D. et al., 2016; Li Y. et al., 2016; Zhang et al., 2017; Cheng et al., 2020).”
BackgroundSirtuins: Key pieces in the host response to pathogens’ puzzle
Silva, R. D. F. E., Bassi, G., Câmara, N. O. S., & Moretti, N. S. (2023) · Molecular Immunology · doi:10.1016/j.molimm.2023.06.010 · Cited by 11
Role of sirtuins in epigenetic regulation and aging control
Samoilova, E. M., Romanov, S. E., Chudakova, D. A., & Laktionov, P. P. (2024) · Vavilov Journal of Genetics and Breeding · doi:10.18699/vjgb-24-26 · Cited by 10
“For example, SIRT5 predominantly deacylates lysine residues which are modified by succinyl, malonyl or glutaryl groups (Du J. et al., 2011; Tan et al., 2014).”
BackgroundSuenkel, B., & Steegborn, C. (2016) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2015.12.004 · Cited by 10
Yu, J., Haldar, M., Mallik, S., & Srivastava, D. K. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152467 · Cited by 9
“More recently, SIRT5 has been found to possess robust desuccinylase, demalonylase and deglutarylase activities but only weak deacylase activity [14, 15].”
BackgroundRecent Advances in Investigating Functional Dynamics of Chromatin
Shi, X., Zhai, Z., Chen, Y., Li, J., & Nordenskiöld, L. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.870640 · Cited by 12
“Glutarylation is a novel histone modification mark that was recently identified at 27 sites of histones (Tan et al., 2014; Bao et al., 2019).”
BackgroundSelf-citationFunctions of Coenzyme A and Acyl-CoA in Post-Translational Modification and Human Disease
Xie, J., Zhang, Y., Zhu, Y., Zheng, M., & Zhu, Y. P. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2909331 · Cited by 10
Self-citationHistone crotonylation in tumors (Review)
Wang, X., Qu, Y., Li, Z., & Xia, Q. (2025) · Molecular and Clinical Oncology · doi:10.3892/mco.2025.2834 · Cited by 10
Li, Z., Tang, W., Lai, Y., Chen, C., Fang, P., Zhou, Y., Fang, L., & Xiao, S. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1013163 · Cited by 9
“SIRT5 functions as a NAD ⁺ -dependent histone deacetylase, requiring NAD ⁺ as a co-substrate for its enzymatic activity [51].”
Unar, A. (2025) · Amino Acids · doi:10.1007/s00726-025-03483-0 · Cited by 9
“Malonylation of mitochondrial and cytosolic proteins involved in central metabolism, including glycolysis, the tricarboxylic acid cycle, and fatty acid β-oxidation, is especially common (Zou et al. 2023; Du et al. 2011; Tan et al. 2014).”
Yuan, T., Keijer, J., Guo, A. H., Lombard, D. B., & de Boer, V. C. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-72833-7 · Cited by 9
Self-citationPropionylation of lysine, a new mechanism of short-chain fatty acids affecting bacterial virulence.
Tang, H., Zhan, Z., Zhang, Y., & Huang, X. (2022) · PubMed · Cited by 12
Self-citationHu, Y., Weng, Y., Jiang, B., Li, X., Zhang, X., Zhao, B., Wu, Q. D., Liang, Z., Zhang, L., & Zhang, Y. (2019) · Science China Chemistry · doi:10.1007/s11426-018-9433-3 · Cited by 9
Self-citationβ-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice
Huynh, F. K., Peterson, B. S., Anderson, K. A., Lin, Z., Coakley, A. J., Llaguno, F. M. S., Nguyen, T.-T. N., Campbell, J. E., Stephens, S. B., Newgard, C. B., et al. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00170.2020 · Cited by 9
Self-citationNucleotide-binding sites can enhance N-acylation of nearby protein lysine residues
James, A. M., Smith, A. C., Ding, S., Houghton, J. W., Robinson, A. J., Antrobus, R., Fearnley, I. M., & Murphy, M. P. (2020) · Scientific Reports · doi:10.1038/s41598-020-77261-1 · Cited by 9
Tasmia, S. A., Ahmed, F. F., Mosharaf, P., Hasan, M., & Mollah, N. H. (2021) · Current Genomics · doi:10.2174/1389202922666210219114211 · Cited by 8
“This modification is transpired in many protein molecules to change their structure and functions in both eukaryotic and prokaryotic organisms [1-3] and altered lysine's charge from +1 to −1 (at physiological pH) and produced comparatively large structural moiety (100 Da), bigger than acetylation…”
Sirtuin insights: bridging the gap between cellular processes and therapeutic applications
Kamal, S., Babar, S., Ali, W., Rehman, K., Hussain, A., & Akash, M. S. H. (2024) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-024-03263-9 · Cited by 8
“Mean-while, SIRT5 is tasked with eliminating negatively charged lysine oscillations through the addition of a glutaryl group, succinyl, acetyl, malonyl, and crotonyl moieties (Tan et al. 2014).”
SIRT5: a potential target for discovering bioactive natural products
Xie, Y., Cai, N., Liu, X., He, L., Ma, Y., Yan, C., Liang, J., Ouyang, S., Luo, A., He, Y., et al. (2025) · Journal of Natural Medicines · doi:10.1007/s11418-024-01871-6 · Cited by 10
Hou, H., Wang, X.-C., Chen, H., Wang, J., Yang, Q., & He, G. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02108-z · Cited by 9
“Different short-chain and long-chain lysine acylations have been identified over the past decade [12–16].”
Hu, D.-W., Huang, C., He, Y., Wei, Y., Hu, S., Cheng, F., Huynh, T. K., Chen, B., Wang, B., Kuan, L., et al. (2025) · Advanced Science · doi:10.1002/advs.202510811 · Cited by 8
Regulation of apoptosis, ferroptosis, and pyroptosis mediated by acetylation
Lu, W., Deng, Y., Liu, M., Hu, Y., Yang, K., Wang, B., Li, Y., wang, G., Ma, L., LIU, J., et al. (2026) · Cell Death Discovery · doi:10.1038/s41420-025-02859-1 · Cited by 9
The role of protein acetylation in regulating mitochondrial fusion and fission
Uddin, G. M., Abbas, R., & Shutt, T. E. (2021) · Biochemical Society Transactions · doi:10.1042/bst20210798 · Cited by 8
Sirtuins—Novel Regulators of Epigenetic Alterations in Airway Inflammation
Wu, S., & Liu, H. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.862577 · Cited by 8
Nutraceuticals for Promoting Longevity
Pavlović, I., Khateb, S., Milisav, I., & Mahajna, J. A. (2020) · Current Nutraceuticals · doi:10.2174/2665978601666200213121512 · Cited by 8
Balaya, R. D. A., Patil, A. H., Modi, P. K., Kandiyil, M. K., Kasaragod, S., Pinto, S. M., Tanneru, N., Sijwali, P. S., & Prasad, T. S. K. (2022) · ACS Omega · doi:10.1021/acsomega.1c03892 · Cited by 7
A new view on functions of the lysine demalonylase activity of SIRT5
Nahálková, J. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121572 · Cited by 8
Functions of lysine 2‐hydroxyisobutyrylation and future perspectives on plants
Zhang, N., Wang, S., Tian, H., Li, S., Liu, L., Li, J., Chen, D., Zhao, S., Yan, X., Niaz, M., et al. (2023) · PROTEOMICS · doi:10.1002/pmic.202300045 · Cited by 8
Role of sirtuins in cardiovascular diseases
Ravi, V., Mishra, S., & Sundaresan, N. R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814118-2.00021-5 · Cited by 7
Dong, N., Ma, H., Liu, X., Dong, L., Liu, L., Shi, Q., & Ju, X. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06599-5 · Cited by 8
“SIRT5 is an important tumor regulator because of its potent deacetylase, desuccinylase, deglutarylase, and demalonylase activities [23, 26, 33, 34].”
BackgroundYang, H., Gao, S., Lu, G., He, J., Dong, J., Zhang, X., Liu, L., Zhong, K., Zha, G., Han, L., et al. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111570 · Cited by 7
Gao, S., Yang, H., Dong, J., Li, A., Zhang, X., Liu, L., Lu, G., Liu, Y., Zha, G., Zhong, K., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.139619 · Cited by 7
Hepatic CBP/p300 Orchestrate Amino Acid‐Driven Gluconeogenesis through Histone Crotonylation
Sheng, C., Li, T., Lin, H., Ma, X., Zhou, F., Li, M., Wang, Y., Wang, S., Tan, J., Chen, J. Y., et al. (2025) · Advanced Science · doi:10.1002/advs.202507635 · Cited by 9
Ming, Z., Luo, T., Zou, Z., Luo, W., Hu, X., Chen, L., Zhou, J., Liu, X., Mingquan, L., Li, J., et al. (2025) · Hepatology Communications · doi:10.1097/hc9.0000000000000769 · Cited by 7
“[39] CPSI is a mitochondrial protein that is homologous to the CPSII domain of CAD protein.”
Liu, J., Zhong, L., & Guo, R. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6635836 · Cited by 7
“Importantly, SIRT5, as a mitochondrial deacetylase, also shows the activity of deacetylase, which separates the substrate protein from the succinyl group [111, 112].”
BackgroundRetractedZhang, Y., & Goetzman, E. S. (2021) · PLoS ONE · doi:10.1371/journal.pone.0256619 · Cited by 6
“The best example of this is glutaryl-CoA dehydrogenase deficiency, which leads to accumulation of glutaryl-CoA, causing increased lysine glutarylation via chemical acylation, ultimately leading to reduced function of other mitochondrial proteins such as carbamoyl phosphate synthase-1 (Cps1) in the urea cycle [29].”
BackgroundSelf-citationXu, X., Hu, X., Dong, J., Xue, Y., Liu, T., & Jin, Q. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.832668 · Cited by 7
“The deacetylase SIRT5 has robust demalonylase, desuccinylase, and deglutarylase activities but very weak deacetylase activity (Du et al., 2011; Peng et al., 2011; Park et al., 2013; Tan et al., 2014).”
BackgroundIntegrative Profiling of Lysine Acylome in Sepsis-Induced Liver Injury
Na, A., Choi, S. Y., Paudel, S., Bae, J., Tan, M., & Lee, S. (2023) · Journal of Proteome Research · doi:10.1021/acs.jproteome.3c00130 · Cited by 7
Self-citationHe, J., Feng, L., Yang, H., Gao, S., Dong, J., Lu, G., Liu, L., Zhang, X., Zhong, K., Guo, S., et al. (2024) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2024.12584 · Cited by 6
Cudré-Cung, H.-P., Remacle, N., do Vale-Pereira, S., Melo, M. G., Henry, H., Ivanišević, J., Schmiesing, J., Mühlhausen, C., Braissant, O., & Ballhausen, D. (2019) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2019.01.009 · Cited by 8
Self-citationA one-step specific assay for continuous detection of sirtuin 2 activity
Dai, Q., Zheng, Z., Xia, F., Liu, P., & Li, M. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.05.007 · Cited by 7
H3K9/18 lactylation regulates DNA damage due to nickel exposure in human bronchial epithelial cells
Xie, X., Wen, C., Peng, Q., Xiang, D., Pan, X., Lan, X., Chen, Z., Hua, X., Wang, G., & Huang, C. (2025) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2025.117347 · Cited by 7
Ren, F., Yang, M., Liu, G., Qi, Y., Li, A., Li, J., & Zheng, L. (2024) · Clinical and Experimental Hypertension · doi:10.1080/10641963.2024.2358030 · Cited by 7
Inhibition of Sirtuin Deacylase Activity by Peroxynitrite
Bohl, K. S., Wynia‐Smith, S. L., Jones, R. A., & Smith, B. C. (2024) · Biochemistry · doi:10.1021/acs.biochem.4c00257 · Cited by 6
Scalable and Purification-Free Synthesis of a Myristoylated Fluorogenic Sirtuin Substrate
Olsen, C. A., Galleano, I., Nielsen, J., & Madsen, A. S. (2017) · Synlett · doi:10.1055/s-0036-1588875 · Cited by 5
Self-citationImproved performance of Lysine Glutarylation PTM using Peptide Evolutionary Features
Ahmad, M. W., Shovan, S. M., Arafat, M. E., Sifat, M. H. R., Hasan, M. A. M., & Shatabda, S. (2019) · International Conference on Electrical, Computer & Telecommunication Engineering (ICECTE) · doi:10.1109/icecte48615.2019.9303533 · Cited by 6
“For numerous metabolic activities like metabolism of amino acids, fatty acids as well as respiration of living cell are highly related to lysine glutarylation PTM [2].”
BackgroundMethodInfluentialChemical Biology Tools for Protein Lysine Acylation
Xie, Y., Du, S., Liu, Z., Liu, M., Xu, Z., Wang, X., Kee, J. X., Yi, F., Sun, H., & Yao, S. Q. (2022) · Angewandte Chemie · doi:10.1002/ange.202200303 · Cited by 6
The Enzymatic Activities of Sirtuins
Lin, H. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813499-3.00004-6 · Cited by 6
The mimics of Nε-acyl-lysine derived from cysteine as sirtuin inhibitors
Wang, C., Wang, F., Chen, X., Zou, Y., Zhu, H., Zhao, Q., Shen, J., Li, Y., Li, Y., & He, B. (2018) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.06.030 · Cited by 6
Sirtuiny – enzymy o wielokierunkowej aktywności katalitycznej
Kratz, E. M., Sołkiewicz, K., Kaczmarek, A., & Piwowar, A. (2021) · Postępy Higieny i Medycyny Doświadczalnej · doi:10.5604/01.3001.0014.7866 · Cited by 6
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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