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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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“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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1 retracted
RETRACTED: Human SIRT6 Promotes DNA End Resection Through CtIP Deacetylation
Kaidi, A., Weinert, B. T., Choudhary, C., & Jackson, S. P. (2010) · Science · doi:10.1126/science.1192049 · Cited by 366 · cited 1×
“In cells, the ability of SIRT6 to promote deacetylation of histones and non-histone proteins (18) seemed at odds with the low in vitro deacetylation rates (13, 19) and with the recently described demyristoylation activity (13).”
BackgroundRetractedTan, M., Luo, H., Lee, S., Jin, F., Yang, J. S., Montellier, E., Buchou, T., Cheng, Z., Rousseaux, S., Rajagopal, N., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.008 · Cited by 1,902 · cited 1×
“Crotonyllysine was identified as a histone modification in several eukaryotic cells types and is associated with active promoters or enhancers (11).”
BackgroundSirtuins in mammals: insights into their biological function
Michán, S., & Sinclair, D. A. (2007) · Biochemical Journal · doi:10.1042/bj20070140 · Cited by 1,750 · cited 1×
“SIRT6 is one of seven members of the mammalian NAD dependent protein deacetylases that are evolutionarily ancient (1).”
BackgroundGenomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., et al. (2006) · Cell · doi:10.1016/j.cell.2005.11.044 · Cited by 1,637 · cited 2×
“Recent studies indicate that SIRT6 plays critical roles in intermediary metabolism and genomic stability (2).”
BackgroundSirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase
Du, J., Zhou, Y., Su, X., Yu, J. J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J. H., Choi, B. H., et al. (2011) · Science · doi:10.1126/science.1207861 · Cited by 1,429 · cited 1×
“The recent observation that SIRT5 prefers succinylated/malonylated substrates helps explain the observed low activity on acetylated substrates (8).”
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BackgroundSIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L. A., Barrett, J. C., et al. (2008) · Nature · doi:10.1038/nature06736 · Cited by 1,111 · cited 1×
“However, several prior studies indicated that SIRT6 acted through deacetylation of histonemarksH3K9Ac (14) and H3K56Ac (15), which modulated HIF1- -dependent (16), NF- B-dependent (17), and c-Myc-dependent (3) pathways.”
BackgroundKawahara, T. L. A., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C. L., Boxer, L. D., Chang, H. Y., et al. (2009) · Cell · doi:10.1016/j.cell.2008.10.052 · Cited by 1,090
The sirtuin SIRT6 regulates lifespan in male mice
Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., Bar-Joseph, Z., & Cohen, H. Y. (2012) · Nature · doi:10.1038/nature10815 · Cited by 1,059 · cited 1×
“SIRT6 overexpression lowers LDL and triglyceride levels, improves glucose tolerance (4), and increases lifespan of male mice (5).”
BackgroundThe Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α
Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R. E., Vadysirisack, D. D., Guimaraes, A., Marinelli, B., Wikstrom, J. D., Nir, T., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.041 · Cited by 1,001 · cited 2×
“However, several prior studies indicated that SIRT6 acted through deacetylation of histonemarksH3K9Ac (14) and H3K56Ac (15), which modulated HIF1- -dependent (16), NF- B-dependent (17), and c-Myc-dependent (3) pathways.”
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Items 301–400 of 661
An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity
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“SIRT2 removes a variety of long-chain acyl groups in addition to acetyl groups in biochemical assays (19, 20), and FLS-359 blocks SIRT2 deacetylation but not demyristoylation (Figure 1F and Supplemental Table 1).”
BackgroundIdentification of new palmitoylated proteins in Toxoplasma gondii
Caballero, M., Alonso, A. M., Deng, B., Attias, M., de Souza, W., & Corvi, M. M. (2016) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2016.01.010 · Cited by 34
“A later report showed that the deacetylase SIRT6 can be activated by free longchain fatty acids such as myristate and palmitate at physiological concentrations and thus, regulate gene transcription [38].”
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“On the other hand, T1AM also resulted in harmonic downregulation of ACSL5, and SIRT6 consistent with the notion of increased oxidation of long-chain FAs and possibly their turnover in the muscle.”
BackgroundInfluentialEpigenetic Regulation of Hepatic Lipogenesis: Role in Hepatosteatosis and Diabetes
Viscarra, J. A., & Sul, H. S. (2020) · Diabetes · doi:10.2337/dbi18-0032 · Cited by 31
An improved fluorogenic assay for SIRT1, SIRT2, and SIRT3
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Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption
Boon, R. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.768996 · Cited by 35
“Interestingly, the activity of SIRT6 was found to be amplified upon binding with free fatty acids (Feldman et al., 2013).”
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Raj, S., Dsouza, L. A., Singh, S. P., & Kanwal, A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.598326 · Cited by 31
The Emerging Role of SIRT7 in Glucose and Lipid Metabolism
Yamagata, K., Mizumoto, T., & Yoshizawa, T. (2023) · Cells · doi:10.3390/cells13010048 · Cited by 33
“SIRT6 preferentially catalyzes deacylation of long-chain fatty-acyl groups from target proteins [7,8].”
BackgroundA glimpse into novel acylations and their emerging role in regulating cancer metastasis
Shi, H., Cui, W., Qin, Y., Chen, L., Yu, T., & Lv, J. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-05104-z · Cited by 35
“Contrastingly, a previous study reported that SIRT1, SIRT2, and SIRT3 tended to remove short-chain acyl groups [31].”
BackgroundWu, G., Fan, X., Cheng, L., Chen, Z., Yi, Y., Liang, J., Huang, X., Yang, N., Yin, J., Guo, W., et al. (2025) · Science Advances · doi:10.1126/sciadv.adx6489 · Cited by 37
Catalysis by protein acetyltransferase Gcn5
Albaugh, B. N., & Denu, J. M. (2020) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2020.194627 · Cited by 33
“However, as the author notes, this data should be considered with caution as SIRT6 is known to be activated by long chain fatty acids and so these effects might be due to SIRT6 activities[108].”
BackgroundSelf-citationEffects of galloflavin and ellagic acid on sirtuin 6 and its anti-tumorigenic activities
Rahnasto‐Rilla, M., Järvenpää, J. P., Huovinen, M., Schroderus, A., Ihantola, E., Küblbeck, J., Khadeer, M., Moaddel, R., & Lahtela-Kakkonen, M. K. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110701 · Cited by 30
“Some natural compounds such as long-chain fatty acids [28], and synthetic compounds have been identified as SIRT6 activators [29,30].”
Pharmacological Advantage of SIRT2-Selective versus pan-SIRT1–3 Inhibitors
Hong, J. Y., Fernandez, I. R., Anmangandla, A., Lü, X., Bai, J. J., & Lin, H. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00331 · Cited by 30
Chemical 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 International Edition · doi:10.1002/anie.202200303 · Cited by 29
A mini-review on Sirtuin activity assays
Li, Y., Liu, T., Liao, S., Li, Y., Lan, Y., Wang, A., Wang, Y., & He, B. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.09.172 · Cited by 34
Selectivity hot-spots of sirtuin catalytic cores
Parenti, M. D., Bruzzone, S., Nencioni, A., & Río, A. D. (2015) · Molecular BioSystems · doi:10.1039/c5mb00205b · Cited by 29
Kawaguchi, M., Ikegawa, S., Ieda, N., & Nakagawa, H. (2016) · ChemBioChem · doi:10.1002/cbic.201600374 · Cited by 28
Liu, X., Yang, Z., Li, H., Luo, W., Duan, W., Zhang, J., Zhu, Z., Liu, M., Li, S., Xin, X., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/7374086 · Cited by 28
“Conversely, the deacetylase activity of SIRT6 depends on the presence of free fatty acid (FFA) [49].”
BackgroundDu, Y., Hu, H., Hua, C., Du, K., & Wei, T. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.06.073 · Cited by 29
Sensitive fluorogenic substrates for sirtuin deacylase inhibitor discovery
Yang, L., Wang, H., Yan, Y., Liu, S., Yu, Z., Huang, M.-Y., Luo, Y., Zheng, X., Yu, Y., & Li, G. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112201 · Cited by 28
Sirtuins and SIRT6 in Carcinogenesis and in Diet
Teixeira, M. C., Sánchez‐López, E., Espina, M., García, M. L., Durazzo, A., Lucarini, M., Novellino, E., Souto, S. B., Santini, A., & Souto, E. B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194945 · Cited by 27
“Moreover, long-chain deacylase activity was found to be an intrinsic activity of most sirtuins [47].”
BackgroundHypothalamic NAD+-Sirtuin Axis: Function and Regulation
Roh, E., & Kim, M. (2020) · Biomolecules · doi:10.3390/biom10030396 · Cited by 30
“SIRT6 effectively deacylates long-chain fatty acids, whilst it has little deacetylase activity [23].”
BackgroundEvolved, Selective Erasers of Distinct Lysine Acylations
Spinck, M., Neumann‐Staubitz, P., Ecke, M., Gasper, R., & Neumann, H. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202002899 · Cited by 27
Lagerwaard, B., Pougovkina, O., Bekebrede, A. F., Brinke, H. T., Wanders, R. J. A., Nieuwenhuizen, A. G., Keijer, J., & de Boer, V. C. J. (2020) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12296 · Cited by 26
“Although it is not clear which enzymes regulate de-propionylation, possibly sirtuins 1-3 hold some de-propionylation activity, at least in vitro.(47,48) In particular activation of sirtuin 3 (SIRT3) could be an interesting strategy due to its cellular localisation within the mitochondria and multiple metabolic targets…”
BackgroundPost-translational lysine ac(et)ylation in health, ageing and disease
Blasl, A., Schulze, S., Qin, C., Graf, L. G., Vogt, R., & Lammers, M. (2021) · Biological Chemistry · doi:10.1515/hsz-2021-0139 · Cited by 30
“Recent data showed that the deacetylase activity can be activated by fatty acids and small molecules mostly carrying a negatively charged carboxylate (Feldman et al. 2013; Klein and Denu 2020; Klein et al. 2020).”
BackgroundSirtuin Oxidative Post-translational Modifications
Kalous, K., Wynia‐Smith, S. L., & Smith, B. C. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.763417 · Cited by 28
“…nitrosylation, oxidation INTRODUCTION TO SIRTUINS Sirtuins are a class of enzymes that remove acetyl and longer-chain acyl groups from lysine residues on proteins in an NAD+-dependent manner, producing O-acyl-ADP-ribose, nicotinamide, and deacylated lysine as products (Feldman et al., 2012).”
BackgroundCyclic peptide-based potent human SIRT6 inhibitors
Liu, J., & Zheng, W. (2016) · Organic & Biomolecular Chemistry · doi:10.1039/c5ob02339d · Cited by 27
Ji, C., Cong, R., Wang, Y., Wang, Y., Zhang, Q., Zhou, X., Xing, Q., & Song, N. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2019.11.32 · Cited by 26
“SIRT6 had been reported to have multiple enzyme activities, including deacetylase activity, de-fatty acylase activity, and monoADP-ribosyltransferase activity (43-45).”
BackgroundVai, A., Noberini, R., Ghirardi, C., de Paula, D. R., Carminati, M., Pallavi, R., Araújo, N. V. P., Varga‐Weisz, P., & Bonaldi, T. (2024) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2024.100799 · Cited by 26
“For what concerns acylation removal, class III NAD(+)-dependent deacetylases (sirtuins) have been proven to have broad-range deacylation activities (12) and class I histone deacetylases are also ef fi cient debutyrylase and decrotonylases (13, 14).”
Mellini, P., Itoh, Y., Elboray, E. E., Tsumoto, H., Li, Y., SUZUKI, M. T., Takahashi, Y., Tojo, T., Kurohara, T., Miyake, Y., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00255 · Cited by 26
Bacterial Sirtuins Overview: An Open Niche to Explore
Gallego‐Jara, J., Ortega, Á., Terol, G. L., Martínez, R. A. S., Díaz, M. C., & Puente, T. D. D. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.744416 · Cited by 27
Jung, Y. H., Chae, C. W., Chang, H. S., Choi, G. E., Lee, H. J., & Han, H. J. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.09.002 · Cited by 26
Kalous, K., Wynia‐Smith, S. L., Summers, S. B., & Smith, B. C. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011988 · Cited by 25
“Compared with Sirt1–3, Sirt6 deacetylase activity is considered weak, although Sirt6 deacetylase activity is more robust against whole protein substrates compared with peptides (15) and is activated by long-chain fatty acids (16, 17).”
BackgroundRegulatory Mechanism of Protein Crotonylation and Its Relationship with Cancer
Yang, S., Fan, X., & Yu, W. (2024) · Cells · doi:10.3390/cells13211812 · Cited by 27
“…et al. used the H3 peptide containing Lys9 to conduct a comprehensive analysis of the activities of seven mammalian silenced regulatory proteins and found that the HDCR activity of Sirt1 and Sirt2 could catalyze the removal of crotonyl modifications from the histone H3K9 peptide in vitro [49].”
BackgroundDevelopment of Activity-Based Chemical Probes for Human Sirtuins
Graham, E., Rymarchyk, S., Wood, M., & Cen, Y. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00754 · Cited by 25
SIRT6 Through the Brain Evolution, Development, and Aging
García-Venzor, A., & Toiber, D. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.747989 · Cited by 28
“Notably, the fetuses presented severe defects in head development, reduced head circumference, and microcephaly, which again points out the role of Sirt6 to ensure the proper development and differentiation of neural cells (Ferrer et al., 2018).”
BackgroundTsai, Y., Chen, S.-L., Peng, S.-L., Tsai, Y.-L., Chang, Z.-M., Chang, V. H.-S., & Ch’ang, H.-J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00687-8 · Cited by 27
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Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates
Yang, F., Su, H., Deng, J. W., Mou, L., Wang, H., Li, R., Dai, Q.-Q., Yan, Y., Qian, S., Wang, Z., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113803 · Cited by 24
Mammalian Sirtuins SIRT4 and SIRT7
Li, S., & Zheng, W. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.001 · Cited by 24
Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase
Troelsen, K. R., Bæk, M., Nielsen, A. L., Madsen, A. S., Rajabi, N., & Olsen, C. A. (2021) · RSC Chemical Biology · doi:10.1039/d0cb00216j · Cited by 24
Sirtuin 2 promotes human cytomegalovirus replication by regulating cell cycle progression
Betsinger, C. N., Justice, J. L., Tyl, M. D., Edgar, J. E., Budayeva, H. G., Abu, Y. F., & Cristea, I. M. (2023) · mSystems · doi:10.1128/msystems.00510-23 · Cited by 23
“However, in addition to functioning as a protein deacetylase, SIRT2 also removes long-chain fatty-acyl, lipoyl, benzoyl, 4-oxononanoyl, and methacrylation groups (33, 45–53).”
BackgroundDong, Z., Yang, C., Tan, J., Dou, C., & Chen, Y. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2021.12.024 · Cited by 23
“clarified that long-chain fatty acids potently enhance SIRT6 enzymatic activity.(152) Quercetin also increases SIRT6 activity at a high concentration by binding to the SIRT6-selective acyl binding channel.”
BackgroundSubstrate-selective small-molecule modulators of enzymes: Mechanisms and opportunities
Lin, H. (2022) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2022.102231 · Cited by 24
Biology, Chemistry, and Pharmacology of Sirtuins
Bedalov, A., Chowdhury, S., & Simon, J. A. (2016) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2016.03.011 · Cited by 23
Fatty acids as histone deacetylase inhibitors: Old biochemistry tales in a new life sciences town
Ediriweera, M. K. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103569 · Cited by 22
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Cao, S., Chen, Z., Yue, L., Jiang, H., Ma, R.-Y., & Dong, L. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.783739 · Cited by 22
New Histone Lysine Acylation Biomarkers and Their Roles in Epigenetic Regulation
Fu, Q., Cat, A., & Zheng, Y. G. (2023) · Current Protocols · doi:10.1002/cpz1.746 · Cited by 24
“For instance, SIRT5 targets negatively charged lysine acylations especially succinylation and malonylation (Peng et al., 2011; M. Tan et al., 2014), and SIRT6 preferentially removes long-chain fatty acyl marks over acetylation from the lysine side chain (Feldman et al., 2013).”
BackgroundCheng, M.-Y., Cheng, Y.-W., Yan, J. X., Hu, X., Zhang, H., Wang, Z., Yin, Q., & Cheng, W. (2016) · PubMed Central · Cited by 22
Rajabi, N., Nielsen, A. L., & Olsen, C. A. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00580 · Cited by 21
Functions of mammalian SIRT4 in cellular metabolism and research progress in human cancer (Review)
Wang, C., Liu, Y., Zhu, Y., & Kong, C. (2020) · Oncology Letters · doi:10.3892/ol.2020.11872 · Cited by 24
“As a member of the sirtuin family, SIRT4 also possesses typical NAD+‐dependent deacetylation activity, but this activity is weak, has substrate specificity, and is associated with cellular lipid metabolism (49).”
BackgroundChemical proteomics approaches to examine novel histone posttranslational modifications
Li, X., & Li, X. D. (2014) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2014.10.015 · Cited by 21
SIRT6 : A potential therapeutic target for diabetic cardiomyopathy
Wu, T., Qu, Y., Xu, S., Wang, Y., Liu, X., & Ma, D. (2023) · The FASEB Journal · doi:10.1096/fj.202301012r · Cited by 23
Adjudin delays cellular senescence through Sirt3‑mediated attenuation of ROS production
Geng, K., Fu, N., Yang, X. Y., & Xia, W. (2018) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2018.3917 · Cited by 22
“…mitochondrial biological processes, including ATP generation, ROS detoxification, nutrient oxidation, mitochondrial dynamics and the unfolded protein response (11‑15) by removing acetyl modifications from mitochondrial proteins (10,16) or other acyl modifications and histone crotonylation (17,18).”
Kawaguchi, M., Ieda, N., & Nakagawa, H. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00315 · Cited by 21
Nitro-fatty acids as activators of hSIRT6 deacetylase activity
Carreño, M., Bresque, M., Machado, M. R., Santos, L., Durán, R., Vitturi, D. A., Escande, C., & Denicola, A. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014883 · Cited by 20
“(43) demonstrated that the low in vitro deacetylase activity of SIRT6 could be activated in the presence of free long-chain fatty acids, particularly oleic and linoleic acid (5-fold increase at 100 mM), and that this activation was not displayed by SIRT1.”
BackgroundMethodInfluentialChen, L., Huang, L., Gu, Y., Li, C., Sun, P., & Xiang, Y. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.133883 · Cited by 21
Sirtuin activators as an anti-aging intervention for longevity
Sah, P., Rai, A. K., & Syiem, D. (2025) · Exploration of Drug Science · doi:10.37349/eds.2025.100881 · Cited by 21
The Epigenetic and Metabolic Language of the Circadian Clock
Sassone‐Corsi, P. (2016) · Research and perspectives in endocrine interactions · doi:10.1007/978-3-319-27069-2_1 · Cited by 20
“In this respect it is noteworthy that not only on NAD, but also on fatty acids, control the activity of SIRT6 (Feldman et al. 2013).”
BackgroundThe sirtuin 6: An overture in skin cancer
Garcia‐Peterson, L. M., Guzmán‐Pérez, G., Krier, C. R., & Ahmad, N. (2019) · Experimental Dermatology · doi:10.1111/exd.14057 · Cited by 21
Research Progress of Sirtuin4 in Cancer
Bai, Y., Yang, J., Cui, Y., Yao, Y., Wu, F., Liu, C., Fan, X., & Zhang, Y. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.562950 · Cited by 20
“Other Activities To screen the activity of recombinant SIRT4 against various acyl histone peptides, SIRT4 displayed dedecanoylase and deoctanoylase activity, as well as exhibited low (but measurable) activity against lipoyl, succinyl, and dodecanoyl substrates (36).”
BackgroundBresque, M., Cal, K., Pérez-Torrado, V., Colman, L., Rodriguez‐Duarte, J., Vilaseca, C., Santos, L., Garat, M. P., Ruiz, S., Evans, F., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101711 · Cited by 21
“Interestingly, the SIRT6 catalytic pocket accommodates long-chain fatty acids, which stimulate the deacetylase activity (14).”
BackgroundAhmed, M. A. H., O'Callaghan, C., Chang, E., Jiang, H., & Vassilopoulos, A. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01462 · Cited by 20
“SIRT2 and SIRT3 exhibit the strongest deacetylation activity compared to other family members (23) and have been shown to regulate the acetylome (24, 25).”
BackgroundA Selective Cyclic Peptidic Human SIRT5 Inhibitor
Liu, J., Huang, Y., & Zheng, W. (2016) · Molecules · doi:10.3390/molecules21091217 · Cited by 18
Bioorthogonal pro-metabolites for profiling short chain fatty acylation
Sinclair, W. R., Shrimp, J. H., Zengeya, T. T., Kulkarni, R. A., Garlick, J. M., Luecke, H. F., Worth, A. J., Blair, I. A., Snyder, N. W., & Meier, J. L. (2017) · Chemical Science · doi:10.1039/c7sc00247e · Cited by 19
Xu, J., Shi, S., Liu, G., Xie, X., Li, J., Bolinger, A. A., Chen, H., Zhang, W., Shi, P., Liu, H., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114998 · Cited by 19
An Update on Lysine Deacylases Targeting the Expanding “Acylome”
Olsen, C. A. (2013) · ChemMedChem · doi:10.1002/cmdc.201300421 · Cited by 20
Wang, H., Liu, S., Yu, Z., Wu, C., Cheng, L., Wang, Y., Chen, K., Zhou, S. W., Chen, Q., Yu, Y., et al. (2017) · RSC Advances · doi:10.1039/c7ra05824a · Cited by 19
Screening of SIRT6 inhibitors and activators: A novel activator has an impact on breast cancer cells
Tenhunen, J., Kučera, T., Huovinen, M., Küblbeck, J., Bisenieks, E., Vı̄gante, B., Ogle, Z., Duburs, G., Doležal, M., Moaddel, R., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111452 · Cited by 19
Lysine crotonylation in disease: mechanisms, biological functions and therapeutic targets
Ji, Y., Liu, S., Zhang, Y., Min, Y., Wei, L., Guan, C., Yu, H., & Zhang, Z. (2025) · Epigenetics & Chromatin · doi:10.1186/s13072-025-00577-7 · Cited by 21
“Class III HDACs, including SIRT1 and SIRT2, were shown to downregulate H3K9cr in vitro using radiometric thin-layer chromatography [38].”
Is nuclear sirtuin SIRT6 a master regulator of immune function?
Pillai, V. B., & Gupta, M. P. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00483.2020 · Cited by 18
Potent Activation of NAD+‑Dependent Deacetylase Sirt7 by Nucleosome Binding
Kuznetsov, V. I., Liu, W. H., Klein, M. A., & Denu, J. M. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.2c00348 · Cited by 17
Self-citationHistone deacetylase inhibitors as antidiabetic agents: Advances and opportunities
Sonthalia, M., Roy, B. S., Chandrawanshi, D., Ganesh, G. V., Jayasuriya, R., Mohandas, S., Rajagopal, S., & Ramkumar, K. M. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175328 · Cited by 18
SIRT6’s function in controlling the metabolism of lipids and glucose in diabetic nephropathy
Wang, Y., Liu, T., Cai, Y., Liu, W., & Guo, J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1244705 · Cited by 19
“When SIRT6 is activated by ribosomes or fatty acids, its deacetylation activity is signi fi cantly enhanced (73, 74).”
BackgroundWang, Y., Fan, J., Meng, X., Shu, Q., Wu, Y., Chu, G., Ji, R., Ye, Y., Wu, X., Shi, J. M., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-55046-8 · Cited by 18
Simple Nε-thioacetyl-lysine-containing cyclic peptides exhibiting highly potent sirtuin inhibition
Huang, Y., Liu, J., Yan, L., & Zheng, W. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.01.086 · Cited by 18
Nakajima, A., Kawaguchi, F., Uemoto, Y., Fukushima, M., Yoshida, E., Iwamoto, E., Akiyama, T., Kohama, N., Kobayashi, E., Honda, T., et al. (2018) · Animal Science Journal · doi:10.1111/asj.12987 · Cited by 18
Alternate deacylating specificities of the archaeal sirtuins Sir2Af1 and Sir2Af2
Ringel, A. E., Roman, C., & Wolberger, C. (2014) · Protein Science · doi:10.1002/pro.2546 · Cited by 18
“containing carboxylates or sulfhydryls.(33) Human SIRT5, which is very active against succinyl lysine, also removes a number of long acyl chains from lysine that vary in length from octanoylation (eight carbons) to dodecanoylation (12 carbons).”
BackgroundInfluentialTan, Y., Xu, Z., Tao, J., Ni, J., Zhao, W., Lu, J. L., & Yao, Y. (2015) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmv121 · Cited by 18
“It was reported that the deacetylase activity of SIRT6 could be activated by long-chain fatty acids [11].”
BackgroundPost-translational modifications of nuclear sirtuins
Zhao, K., & Zhou, Z. (2019) · Genome Instability & Disease · doi:10.1007/s42764-019-00001-x · Cited by 19
Fan, S., Chen, W., Li, Y., Guo, K., Hui, T., Ye, J., Zhou, Z., Tan, M., Wei, H., Huang, X., et al. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156395 · Cited by 17
Adhikari, S., Guha, D., Mohan, C., Mukherjee, S., Tyler, J. K., & Das, C. (2022) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-07634-3_1 · Cited by 19
Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
Wu, L., Wang, X., Jiang, J., Chen, Y., Peng, B., & Jin, W. (2023) · Open Medicine · doi:10.1515/med-2023-0812 · Cited by 17
“showed that rhubarb phenols significantly up-regulated the r RNA levels of MGLL and HSL, which are key enzymes in lipolysis, and also the expression of β-oxidation-related genes in fatty acids [68].”
BackgroundSubstrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**
Bolding, J. E., Nielsen, A. L., Jensen, I., Hansen, T. N., Ryberg, L. A., Jameson, S. T., Harris, P., Peters, G. H. J., Denu, J. M., Rogers, J. M., et al. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202314597 · Cited by 17
Self-citationMathias, R. A., Greco, T., & Cristea, I. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3667-0_15 · Cited by 13
“The conventional approach to discover new sirtuin enzymatic activities has been to screen various acyl-modified histone peptides with recombinant SIRT proteins in in vitro reactions [19].”
BackgroundOlesen, S. V., Rajabi, N., Svensson, B., Olsen, C. A., & Madsen, A. S. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00306 · Cited by 16
Screening and profiling assays for HDACs and sirtuins
Howitz, K. T. (2015) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2015.10.008 · Cited by 17
“Similarly, SIRT6 [76–78], SIRT2 and other sirtuins [77] have recently been shown to harbour defattyacylation activities.”
BackgroundSIRT7 clears the way for DNA repair
Paredes, S., & Chua, K. F. (2016) · The EMBO Journal · doi:10.15252/embj.201694904 · Cited by 17
“Recent studies have shown that some mammalian sirtuin enzymes can catalyze deacylation of longer chain fatty acyl modifications on histones or other proteins, such as myristoylation, succinylation, and crotonylation (Feldman et al , 2013).”
Investigating Deformylase and Deacylase Activity of Mammalian and Bacterial Sirtuins
Seidel, J., Klockenbusch, C., & Schwarzer, D. (2015) · ChemBioChem · doi:10.1002/cbic.201500611 · Cited by 18
Photo Cross‐Linking Probes Containing ϵ‐ N ‐Thioacyllysine and ϵ‐ N ‐Acyl‐(δ‐aza)lysine Residues
Bæk, M., Martín‐Gago, P., Laursen, J. S., Madsen, J. L. H., Chakladar, S., & Olsen, C. A. (2020) · Chemistry – A European Journal · doi:10.1002/chem.201905338 · Cited by 16
Sirtuins in osteoarthritis: current understanding
Liu, Y., Zhang, Z., Liu, C., & Zhang, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1140653 · Cited by 18
Protein lysine crotonylation in cellular processions and disease associations
Zhao, H., Han, Y., Zhou, P., Guan, H., & Gao, S. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.06.029 · Cited by 19
Avrahami, E. M., Levi, S., Zajfman, E., Regev, C., Ben‐David, O., & Arbely, E. (2018) · ACS Synthetic Biology · doi:10.1021/acssynbio.8b00314 · Cited by 15
SIRT6 serves as a polyhedron in glycolytic metabolism and ageing-related diseases
Yuan, Z., Zeng, Y., Tian, Y., Wang, S., Hong, B., & Yang, M. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111765 · Cited by 14
Gao, Y., Peng, K., Wang, Y., Guo, Y., Zeng, C., Hua, R., Liu, Q., Li, X., Qiu, Y., & Wang, Z. (2023) · Food Science and Human Wellness · doi:10.1016/j.fshw.2023.03.043 · Cited by 15
The role of structural biology in the design of sirtuin activators
Fiorentino, F., Mai, A., & Rotili, D. (2023) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2023.102666 · Cited by 15
Fan, S., Kong, C., Zhou, R., Zheng, X., Ren, D., & Yin, Z. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c08332 · Cited by 17
Metadata
- 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
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