Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins
Open accessAbstract
Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD + -dependent protein deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long-chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor deacetylase in vitro , but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small-molecule activators of SIRT6. Background: Sirtuins regulate metabolism, genome maintenance, and stress responses. Results: Long-chain free fatty acids stimulate SIRT6 deacetylase, and sirtuins display distinct but overlapping specificity for diverse acylated peptides. Conclusion: SIRT6 is activated by biologically relevant fatty acids, and long-chain deacylation is a general feature of sirtuins. Significance: Discovery of endogenous, small-molecule activators of SIRT6 demonstrates the therapeutic potential of compounds that promote SIRT6 function.
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Some sirtuin family members mediate non-acetyl lysine acylations, such as succinylation, malonylation and fatty acid acylation, whose cellular functions are poorly understood.
“Additionally, some members of the sirtuin family mediate non-acetyl lysine acylations (for example, succinylation, malonylation and fatty acid acylation)13–15, the cellular functions of which are so far poorly understood16.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [13]
Sirtuins 1, 2 and 3 have been shown to be decrotonylases in vitro.
“Unsurprisingly, given the range of their potential substrates, sirtuins 1, 216 and 317 were shown to be decrotonylases in vitro.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [16]
Decrotonylase activity has been described for HDAC1-3 and Sirtuins 1-3.
“To date, decrotonylase activity has been described for HDAC1-3 and Sirtuins 1-316–18,21,22.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [16]
This is the first report of a zinc-dependent HDAC with defatty-acylation activity.
“While some of the sirtuins, the NAD+-dependent HDACs, have been recognized as protein defatty-acylases,12,16,17 this is the first report of a zinc-dependent HDAC possessing this enzymatic activity.”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [16]
Several NAD+-dependent deacetylases, SIRT1, SIRT2, SIRT3 and SIRT6, have been previously reported to possess lysine defatty-acylation activities.
“Several NAD+-dependent deacetylase, SIRT1, SIRT2, SIRT3 and SIRT6, have been previously reported to possess lysine defatty-acylation activities.15-17”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [16]
SIRT1, 2, 3 and SIRT6 are capable of hydrolyzing long chain fatty acyl groups from lysine residues.
“and SIRT1, 2, 3 and SIRT6 are capable of hydrolyzing long chain fatty acyl groups from lysine residues.15-17”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [16]
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SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion
Anderson, K. A., Huynh, F. K., Fisher-Wellman, K., Stuart, J. D., Peterson, B. S., Douros, J. D., Wagner, G. R., Thompson, J. W., Madsen, A. S., Green, M. F., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.003 · Cited by 326 · see citing works
“, 2013b), but recombinant SIRT4 does not catalyze deacetylation on a variety of substrates (Feldman et al., 2013; Verdin et al., 2004).”
BackgroundResultInfluentialMetabolic Regulation of Histone Post-Translational Modifications
Fan, J., Krautkramer, K. A., Feldman, J. L., & Denu, J. M. (2015) · ACS Chemical Biology · doi:10.1021/cb500846u · Cited by 334 · see citing works
“Although all seven mammalian sirtuins possess highly conserved NAD+-binding and catalytic domains, they have divergent biological roles due to differences in subcellular location, tissue expression, and substrate specificity (39, 41).”
BackgroundSelf-citationEffects of Oxidative Stress on Mesenchymal Stem Cell Biology
Denu, R. A., & Hematti, P. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/2989076 · Cited by 331 · see citing works
“Recent studies have demonstrated the possibility of activating SIRT6 with longchain fatty acids [121], whichmay represent away tomodulate MSC function and longevity.”
BackgroundProtein acetylation in metabolism – metabolites and cofactors
Menzies, K. J., Zhang, H., Katsyuba, E., & Auwerx, J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.181 · Cited by 331 · see citing works
Carrico, C., Meyer, J. G., He, W., Gibson, B. W., & Verdin, E. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.01.016 · Cited by 331 · see citing works
“Other lysine acylations targeted by sirtuins Evidence is also emerging that most sirtuins may act on multiple acyl substrates, at least in vitro ((Feldman, Baeza, and Denu 2013)).”
BackgroundBao, X., Wang, Y., Li, X., Li, X.-M., Liu, Z., Yang, T., Wong, C. F., Zhang, J., Hao, Q., & Li, X. D. (2014) · eLife · doi:10.7554/elife.02999 · Cited by 324 · see citing works
“Recently, using a radioactive thin layer chromatography based assay, Denu et al. demonstrated that Sirt1 and Sirt2 can catalyze the removal of a crotonyl group from a histone H3K9Cr peptide (Feldman et al., 2013).”
Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases
Wagner, G. R., & Hirschey, M. D. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.03.027 · Cited by 319 · see citing works
“Importantly, these modifications can be removed by HDACs and sirtuins in vitro (Feldman et al., 2013; Madsen and Olsen, 2012).”
Circadian Clock Control of Liver Metabolic Functions
Reinke, H., & Asher, G. (2016) · Gastroenterology · doi:10.1053/j.gastro.2015.11.043 · Cited by 321 · see citing works
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“SIRT1-3 display robust deacetylation activity, while SIRT4-7 have no detectable or very weak deacetylase activity and show diverse substrate specificity (Hirschey, 2011; Feldman et al, 2013).”
BackgroundMechanisms and Dynamics of Protein Acetylation in Mitochondria
Baeza, J., Smallegan, M. J., & Denu, J. M. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.12.006 · Cited by 312 · see citing works
“deacetylation activity [26].”
Self-citationMitochondrial Sirtuins and Molecular Mechanisms of Aging
van de Ven, R. A. H., Santos, D., & Haigis, M. C. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.02.005 · Cited by 309 · see citing works
Selective Sirt2 inhibition by ligand-induced rearrangement of the active site
Rumpf, T., Schiedel, M., Karaman, B., Roessler, C., North, B. J., Lehotzky, A., Oláh, J., Ladwein, K. I., Schmidtkunz, K., Gajer, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms7263 · Cited by 302 · see citing works
“(a) Chemical structure of SirReal2 (1).”
Wei, W., Liu, X., Chen, J., Gao, S., Lu, L., Zhang, H., Ding, G., Wang, Z., Chen, Z., Shi, T., et al. (2017) · Cell Research · doi:10.1038/cr.2017.68 · Cited by 304 · see citing works
Partitioning Circadian Transcription by SIRT6 Leads to Segregated Control of Cellular Metabolism
Masri, S., Rigor, P., Cervantes, M., Ceglia, N., Sebastian, C., Xiao, C., Roqueta-Rivera, M., Deng, C., Osborne, T. F., Mostoslavsky, R., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.050 · Cited by 292 · see citing works
Sirtuins: guardians of mammalian healthspan
Giblin, W., Skinner, M. E., & Lombard, D. B. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.04.007 · Cited by 280 · see citing works
“In vitro deacetylation of an H3K9Ac peptide by SIRT6 is stimulated by addition of physiologic concentrations of several long-chain fatty acids, representing a mode of endogenous catalytic regulation distinct from NAD+ concentration [26].”
BackgroundIdentification of a cellularly active SIRT6 allosteric activator
Huang, Z., Zhao, J., Deng, W., Chen, Y., Shang, J., Song, K., Zhang, L., Wang, C., Lu, S., Yang, X., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0150-0 · Cited by 277 · see citing works
Schiedel, M., Herp, D., Hammelmann, S., Swyter, S., Lehotzky, A., Robaa, D., Oláh, J., Ovádi, J., Sippl, W., & Jung, M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01872 · Cited by 275 · see citing works
Fatty acylation of proteins: The long and the short of it
Resh, M. D. (2016) · Progress in Lipid Research · doi:10.1016/j.plipres.2016.05.002 · Cited by 277 · see citing works
“Processing of TNFα involves demyristoylation by Sirt6, an event that is required for efficient secretion of the mature form of TNFalpha into the media[47].”
BackgroundInfluentialChen, B., Sun, Y., Niu, J., Jarugumilli, G. K., & Wu, X. (2018) · Cell chemical biology · doi:10.1016/j.chembiol.2018.05.003 · Cited by 274 · see citing works
“However, free fatty acids, including myristic, oleic, and linoleic acids, at physiological concentrations induce up to a 35-fold increase of SIRT6 catalytic efficiency (Feldman et al., 2013).”
BackgroundSirtuins in Epigenetic Regulation
Jing, H., & Lin, H. (2015) · Chemical Reviews · doi:10.1021/cr500457h · Cited by 271 · see citing works
Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology
Kumar, S., & Lombard, D. B. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1458071 · Cited by 264 · see citing works
“2014) and long-chain deacylase (Feldman et al. 2013; Wang et al. 2016) activities, and SIRT7 mediates deacetylation (Barber et al.”
BackgroundSIRT6: Novel Mechanisms and Links to Aging and Disease
Tasselli, L., Zheng, W., & Chua, K. F. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.10.002 · Cited by 267 · see citing works
“, myristic acid), suggesting that in vivo, efficient deacetylation of known or novel SIRT6 substrates [19_TD$DIFF]could depend on endogenous FFA activators that fluctuate with metabolic conditions [15].”
InfluentialReprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?
Wyngene, L. V., Vandewalle, J., & Libert, C. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708712 · Cited by 264 · see citing works
“The catalytic activity of SIRT6, a member of the class III HDACs, was shown to be increased by certain FFAs up to 35-fold in vitro (Feldman et al, 2013).”
BackgroundInterplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches
Wong, C. C., Qian, Y., & Yu, J. Q. (2017) · Oncogene · doi:10.1038/onc.2016.485 · Cited by 260 · see citing works
A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation
Wagner, G. R., Bhatt, D. P., O’Connell, T. M., Thompson, J. W., Dubois, L. G., Backos, D. S., Yang, H., Mitchell, G. A., Ilkayeva, O. R., Stevens, R. D., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.006 · Cited by 258 · see citing works
“Modifications of lysine residues with long-chain acyl groups are removed by SIRT6 (Jiang et al., 2013); additionally, several sirtuins remove longchain acyl-lysine modifications in vitro (Feldman et al., 2013; Madsen et al., 2016).”
Liu, S., Yu, H., Liu, Y., Liu, X., Zhang, Y., Bu, C., Yuan, S., Chen, Z., Xie, G., Li, W., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.07.011 · Cited by 258 · see citing works
“It was also shown that SIRT1, SIRT2, and SIRT3 could act as decrotonylases (Bao et al., 2014; Feldman et al., 2013).”
BackgroundThe Substrate Specificity of Sirtuins
Bheda, P., Jing, H., Wolberger, C., & Lin, H. (2016) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014537 · Cited by 247 · see citing works
Histones: At the Crossroads of Peptide and Protein Chemistry
Müller, M. M., & Muir, T. W. (2015) · Chemical Reviews · doi:10.1021/cr5003529 · Cited by 247 · see citing works
Jing, H., Hu, J., He, B., Abril, Y. L. N., Stupinski, J., Weiser, K., Carbonaro, M., Chiang, Y., Southard, T. L., Giannakakou, P., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.02.007 · Cited by 234 · see citing works
“Recent studies suggested that different sirtuins may have different acyl group specificity (Du et al., 2011; Feldman et al., 2013; Jiang et al., 2013; Zhu et al., 2012), which can be utilized to design inhibitors specific for different sirtuins (He et al.”
SIRT6, a Mammalian Deacylase with Multitasking Abilities
Chang, A. R., Ferrer, C. M., & Mostoslavsky, R. (2019) · Physiological Reviews · doi:10.1152/physrev.00030.2018 · Cited by 236 · see citing works
Barnes, C. E., English, D. M., & Cowley, S. M. (2019) · Essays in Biochemistry · doi:10.1042/ebc20180061 · Cited by 225 · see citing works
Flynn, E. M., Huang, O. W., Poy, F., Oppikofer, M., Bellon, S. F., Tang, Y., & Cochran, A. G. (2015) · Structure · doi:10.1016/j.str.2015.08.004 · Cited by 222 · see citing works
“In addition, short-chain fatty acyl modifications (propionyl, butyryl, crotonyl) can be removed by various sirtuins (Bao et al., 2014; Feldman et al., 2013; Garrity et al., 2007; Smith and Denu, 2007).”
BackgroundSirtuins, epigenetics and longevity
Wątroba, M., Dudek, I., Skoda, M., Stangret, A., Rzodkiewicz, P., & Szukiewicz, D. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.001 · Cited by 222 · see citing works
“In some metabolic contexts in the liver, SIRT1 and SIRT6 can backup one another: low-carbohydrate, high-fat diet can suppress SIRT1, but at the same time, large amounts of FFA-derived acyl groups can activate SIRT6 (Feldman, Baeza, and Denu 2013).”
BackgroundSIRT3 regulates progression and development of diseases of aging
McDonnell, E., Peterson, B. S., Bomze, H. M., & Hirschey, M. D. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2015.06.001 · Cited by 217 · see citing works
“SIRT3 has also been reported to remove other acyl modifications such as long-chain fatty acyl modifications and histone decrotonylation [13, 14], although understanding the biological relevance of these modifications requires further work.”
Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases
Hershberger, K. A., Martin, A. S., & Hirschey, M. D. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.5 · Cited by 218 · see citing works
Undercover: gene control by metabolites and metabolic enzymesPreprint
van der Knaap, J. A., & Verrijzer, C. P. (2016) · Genes & Development · doi:10.1101/gad.289140.116 · Cited by 213 · see citing works
“Conversely, long chain fatty acids stimulate SIRT6 deacetylation in vitro (Feldman et al. 2013).”
BackgroundGlobal profiling of crotonylation on non-histone proteins
Xu, W., Wan, J., Zhan, J., Li, X., He, H., Shi, Z., & Zhang, H. (2017) · Cell Research · doi:10.1038/cr.2017.60 · Cited by 213 · see citing works
Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio
Anderson, K. A., Madsen, A. S., Olsen, C. A., & Hirschey, M. D. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.09.005 · Cited by 210 · see citing works
“This assay was applied for the discoveries of desuccinylation and deglutarylation by SIRT5 [47, 48], hydrolysis of hydrocarbon-based acyl groups of varying length by the action of SIRT1–3 and 6 [49, 50], and most recently for the discovery of SIRT4 deacylase activity [51].”
MethodBeyond histone acetylation—writing and erasing histone acylations
Zhao, S., Zhang, X., & Li, H. (2018) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2018.10.001 · Cited by 207 · see citing works
The Role of Sirtuins in Cellular Homeostasis
Kupis, W., Pałyga, J., Tomal, E., & Niewiadomska, E. (2016) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-016-0492-6 · Cited by 200 · see citing works
Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age‐related disorders
Srivastava, S. (2016) · Clinical and Translational Medicine · doi:10.1186/s40169-016-0104-7 · Cited by 193 · see citing works
“deacylases harboring lysine deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity [37, 40, 88, 104], or an ADP-ribosyltransferase activity [36, 48].”
BackgroundLi, F., Liu, J., Bao, R., Yan, G., Feng, X., Xu, Y., Sun, Y., Yan, W., Ling, Z., Xiong, Y., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-02950-5 · Cited by 197 · see citing works
Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2
Xiong, X., Panchenko, T., Yang, S., Zhao, S., Yan, P., Zhang, W., Xie, W., Li, Y., Zhao, Y., Allis, C. D., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2218 · Cited by 192 · see citing works
Jing, H., Hu, J., He, B., Abril, Y. L. N., Stupinski, J., Weiser, K., Carbonaro, M., Chiang, Y., Southard, T. L., Giannakakou, P., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.04.005 · Cited by 190 · see citing works
Feldman, J. L., Dittenhafer‐Reed, K. E., Kudo, N., Thelen, J. N., Ito, A., Yoshida, M., & Denu, J. M. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00150 · Cited by 189 · see citing works
“monitors the formation of deacylated product.(1)”
BackgroundInfluentialSelf-citationDual Tumor Suppressor and Tumor Promoter Action of Sirtuins in Determining Malignant Phenotype
Carafa, V., Altucci, L., & Nebbioso, A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00038 · Cited by 183 · see citing works
“In addition, it was recently found to exhibit deacylase activity by removing myristoyl and palmitoyl groups (long-chain fatty acyl groups) from lysine residues (Feldman et al., 2013).”
BackgroundEfficient Demyristoylase Activity of SIRT2 Revealed by Kinetic and Structural Studies
Teng, Y.-B., Jing, H., Aramsangtienchai, P., He, B., Khan, S., Hu, J., Lin, H., & Hao, Q. (2015) · Scientific Reports · doi:10.1038/srep08529 · Cited by 184 · see citing works
Christensen, D. G., Xie, X., Basisty, N., Byrnes, J., McSweeney, S. M., Schilling, B., & Wolfe, A. J. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01604 · Cited by 179 · see citing works
HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2
Cao, J., Sun, L., Aramsangtienchai, P., Spiegelman, N. A., Zhang, X., Huang, W., Seto, E., & Lin, H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815365116 · Cited by 189 · see citing works
“The studies with HDAC11 suggest that the zinc-dependent HDACs are similar to the sirtuin family of HDACs, where several members preferentially recognize acyl lysine modifications other than acetyl lysine, while some can remove multiple modifications with similar efficiencies (11, 13).”
BackgroundChamberlain, K. A., Huang, N., Xie, Y., Licausi, F., Li, S., Li, Y., & Sheng, Z. (2021) · Neuron · doi:10.1016/j.neuron.2021.08.011 · Cited by 181 · see citing works
The Metabolic Impact on Histone Acetylation and Transcription in Ageing
Peleg, S., Feller, C., Ladurner, A. G., & Imhof, A. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.05.008 · Cited by 178 · see citing works
“It is worth mentioning that recent data suggest that some KAT/KDAC effects may occur not through modulation of acetylation but rather by the modulation of acylation marks such as malonylation, glutarylation, or succinylation [105,106].”
BackgroundEmerging roles of SIRT6 in human diseases and its modulators
Liu, G., Chen, H., Liu, H., Zhang, W., & Zhou, J. (2020) · Medicinal Research Reviews · doi:10.1002/med.21753 · Cited by 177 · see citing works
“A continuous study from Denu group revealed relatively low in vitro deacetylase activity of SIRT6, which probably stems from a unique splayed configuration between the Rossmann fold and the zinc‐binding domain.(31,34) However, long‐chain fatty acids (FAs) were found to”
BackgroundInfluentialHIV latency is reversed by ACSS2-driven histone crotonylation
Jiang, G., Nguyen, D. X., Archin, N. M., Yukl, S. A., Méndez‐Lagares, G., Tang, Y., Elsheikh, M. M., Thompson, G. R., Hartigan-O’Connor, D. J., Margolis, D. M., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci98071 · Cited by 169 · see citing works
Structure of p300 in complex with acyl-CoA variants
Kaczmarska, Z., Ortega, E. M., Goudarzi, A., Huang, H., KIM, S. ‐., Márquez, J. A., Zhao, Y., Khochbin, S., & Panne, D. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2217 · Cited by 174 · see citing works
Sirtuin Inhibitors as Anticancer Agents
Hu, J., Jing, H., & Lin, H. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.44 · Cited by 168 · see citing works
Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules
You, W., Rotili, D., Li, T., Kambach, C., Meleshin, M., Schutkowski, M., Chua, K. F., Mai, A., & Steegborn, C. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201610082 · Cited by 170 · see citing works
Histone deacetylase 11 is a fatty-acid deacylase
Kutil, Z., Novakova, Z., Meleshin, M., Mikesova, J., Schutkowski, M., & Barinka, C. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00942 · Cited by 174 · see citing works
Understanding the Function of Mammalian Sirtuins and Protein Lysine Acylation
Wang, M., & Lin, H. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-082520-125411 · Cited by 171 · see citing works
Sirtuins and their Biological Relevance in Aging and Age-Related Diseases
Zhao, L., Cao, J., Hu, K., He, X., Dou, Y., Tong, T., & Han, L. (2020) · Aging and Disease · doi:10.14336/ad.2019.0820 · Cited by 174 · see citing works
Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1
Najt, C. P., Khan, S. A., Heden, T. D., Witthuhn, B. A., Perez, M., Heier, J. L., Mead, L. E., Franklin, M. P., Karanja, K. K., Graham, M. J., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.12.003 · Cited by 161 · see citing works
Zhang, G., Deng, Y.-J., Xie, Q.-Q., Ren, E., Ma, Z., He, X., Gao, Y., & Kang, X. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.04.016 · Cited by 157 · see citing works
Yu, H., Bu, C., Liu, Y., Gong, T., Liu, X., Liu, S., Peng, X., Zhang, W., Peng, Y., Yang, J., et al. (2020) · Science Advances · doi:10.1126/sciadv.aay4697 · Cited by 157 · see citing works
“It has been reported that classic histone acetyltransferases p300, pCAF, and MOF also have histone crotonyltransferase activity (3, 4), while classic histone deacetylases HDAC1/2/3 and SIRT1/2/3 are able to remove Kcr under different conditions (5, 6).”
BackgroundSIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases
Guo, Z., Li, P., Ge, J., & Li, H. (2022) · Aging and Disease · doi:10.14336/ad.2022.0413 · Cited by 160 · see citing works
“Aging and Disease • Volume 13, Number 6, December 2022 1812 in vivo [15, 23, 38].”
BackgroundNatural polyphenols as sirtuin 6 modulators
Rahnasto‐Rilla, M., Tyni, J., Huovinen, M., Jarho, E. M., Kulikowicz, T., Ravichandran, S., Bohr, V. A., Ferrucci, L., Lahtela-Kakkonen, M. K., & Moaddel, R. (2018) · Scientific Reports · doi:10.1038/s41598-018-22388-5 · Cited by 149 · see citing works
SIRT6 is a DNA double-strand break sensor
Onn, L., Portillo, M., Ilic, S., Cleitman, G., Stein, D., Kaluski, S., Shirat, I., Slobodnik, Z., Einav, M., Erdel, F., et al. (2020) · eLife · doi:10.7554/elife.51636 · Cited by 145 · see citing works
“Through these functions, SIRT6 regulates DNA damage repair (DDR), telomere maintenance, and gene expression (Feldman et al., 2013; Jiang et al., 2013; Kugel and Mostoslavsky, 2014).”
BackgroundHistone deacetylase 11 is an ε-N-Myristoyllysine hydrolase
Moreno-Yruela, C., Galleano, I., Madsen, A. S., & Olsen, C. A. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.04.007 · Cited by 149 · see citing works
Das, U. N. (2021) · Biomolecules · doi:10.3390/biom11020241 · Cited by 142 · see citing works
Metabolic Signaling to ChromatinPreprint
Berger, S. L., & Sassone‐Corsi, P. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019463 · Cited by 142 · see citing works
Robey, R. B., Weisz, J., Kuemmerle, N. B., Salzberg, A. C., Berg, A. S., Brown, D. G., Maurer, L. L., Palorini, R., Al‐Mulla, F., Al-Temaimi, R. A., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv037 · Cited by 138 · see citing works
“Sirtuins are NAD+-dependent deacylases with established roles in intermediary metabolism, cellular stress responsiveness and DNA maintenance and repair (206,207).”
BackgroundKelly, R. D. W., Chandru, A., Watson, P. J., Song, Y., Blades, M., Robertson, N. S., Jamieson, A. G., Schwabe, J. W. R., & Cowley, S. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-32927-9 · Cited by 138 · see citing works
Functions and mechanisms of lysine crotonylation
Wan, J., Liu, H., Chu, J., & Zhang, H. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14650 · Cited by 138 · see citing works
Protein lysine crotonylation: past, present, perspective
Jiang, G., Li, C., Lü, M. K., Lu, K., & Li, H. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03987-z · Cited by 138 · see citing works
“Both class I and III HDACs were reported as histone decrotonaylases (HDCRs) [2].”
BackgroundInfluentialLamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair
Ghosh, S., Liu, B., Wang, Y., Hao, Q., & Zhou, Z. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.006 · Cited by 129 · see citing works
“A recent study claimed that long-chain fatty acids stimulate SIRT6 activity (Feldman et al., 2013).”
BackgroundSirtuins, metabolism, and DNA repair
Choi, J.-E., & Mostoslavsky, R. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2014.05.005 · Cited by 132 · see citing works
“stimulated a thousand fold by free FA (FFA), performing as robust as any of the other sirtuins [60].”
BackgroundInfluentialRibas‐Latre, A., & Eckel‐Mahan, K. L. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2015.12.006 · Cited by 133 · see citing works
“Like SIRT1, SIRT6 is sensitive to cellular NADþ levels and can bind to the CLOCK:BMAL1 heterodimer directly to modulate target gene expression [121]; but unlike SIRT1, SIRT6 appears to exert its chromatin effects in part via its sensitivity to specific fatty acids (FFAs) like myristic, oleic, or linoleic acid [145].”
BackgroundNuclear metabolism and the regulation of the epigenome
Boon, R., da Silveira, G. G., & Mostoslavsky, R. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00285-4 · Cited by 125 · see citing works
Lu, R. J., Taylor, S., Contrepois, K., Kim, M., Bravo, J. I., Ellenberger, M., Sampathkumar, N. K., & Benayoun, B. A. (2021) · Nature Aging · doi:10.1038/s43587-021-00086-8 · Cited by 128 · see citing works
- Authors
- Feldman, J. L., Baeza, J., & Denu, J. M.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Denu, John M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 288
- Issue
- 43
- Pages
- 31350-31356
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3829447
- OpenAlex
- W2061576857
- Cited by
- 637
- References
- 38
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 36 · 2023: 44 · 2022: 50 · 2021: 61 · 2020: 55 · 2019: 53 · 2018: 66 · 2017: 47 · 2016: 73 · 2015: 53 · 2014: 37 · 2013: 5
- FWCI
- 26.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA014520)
- National Institute of General Medical Sciences (GM-065386, R01GM065386, T32GM007215, R37GM059785)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- SIRT6, sirtuins, long-chain fatty acids, lysine acylation, histone H3, free fatty acids, enzyme activation, substrate specificity, myristoylation, NAD+-dependent deacetylase
- MeSH terms
- Acylation, Enzyme Activation, Fatty Acids, Histones, Humans, Hydrolysis, Sirtuins, Lipoylation, Sirtuin 1, Sirtuin 2, Sirtuin 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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