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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).”
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“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
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“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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Metabolism and acetylation in innate immune cell function and fate
Cameron, A. M., Lawless, S. J., & Pearce, E. J. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.10.003 · Cited by 65
A Click Chemistry Approach Reveals the Chromatin-Dependent Histone H3K36 Deacylase Nature of SIRT7
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Uncovering Robust Delactoylase and Depyruvoylase Activities of HDAC Isoforms
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Sirtuin-dependent clock control
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SIRT4 is the last puzzle of mitochondrial sirtuins
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A Small‐Molecule SIRT2 Inhibitor That Promotes K‐Ras4a Lysine Fatty‐Acylation
Spiegelman, N. A., Hong, J. Y., Hu, J., Jing, H., Wang, M., Price, I. R., Cao, J., Yang, M., Zhang, X., & Lin, H. (2019) · ChemMedChem · doi:10.1002/cmdc.201800715 · Cited by 61
An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethalityPreprint
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“6 μm; Phenomenex) bymonitoring the formation of the deacylated product at 214 nm (Feldman et al. 2013).”
BackgroundMethodInfluentialSelf-citationThe Emerging Role of HDACs: Pathology and Therapeutic Targets in Diabetes Mellitus
Dewanjee, S., Vallamkondu, J., Kalra, R. S., Chakraborty, P., Gangopadhyay, M., Sahu, R., Medala, V. K., John, A. A., Reddy, P. H., Feo, V. D., et al. (2021) · Cells · doi:10.3390/cells10061340 · Cited by 63
“However, the genetic inhibition approach revealed that only HDAC3 inhibition is sufficient to prevent cytokine-induced β cell damage [73, 157].”
BackgroundInfluentialSIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage
Rizzo, A., Iachettini, S., Salvati, E., Zizza, P., Maresca, C., D’Angelo, C., Benarroch, D., Capolupo, A., Gaudio, F. D., Cosconati, S., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1202 · Cited by 66
“Notably, many functions of SIRT6 are linked to its ability to deacetylate and catalyze mono-ADP-ribosylation of nonhistone proteins (52–54), and deacetylate long-chain fatty acil groups (55).”
BackgroundZhang, Y., Zhou, F., Bai, M., Liu, Y., Zhang, L., Zhu, Q., Bi, Y., Ning, G., Zhou, L., & Wang, X. Q. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1349-z · Cited by 62
Delaney, K., Tan, M., Zhu, Z., Gao, J., Dai, L., Kim, S., Ding, J., He, M., Halabelian, L., Yang, L., et al. (2021) · Cell Discovery · doi:10.1038/s41421-021-00344-4 · Cited by 60
“a Synthetic peptides consisting of the first 20 amino acid residues of the H4 histone, H4 (1-20), were”
BackgroundMethodGottlieb, C. D., Zhang, S., & Linder, M. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.691147 · Cited by 59
Kudo, N., Ito, A., Arata, M., Nakata, A., & Yoshida, M. (2018) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2017.0070 · Cited by 60
SIRT6 Widely Regulates Aging, Immunity, and Cancer
Li, Y., Jin, J., & Wang, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.861334 · Cited by 61
“SIRT6 shows poor deacetylase activity in vitro (32); however, free fatty acids could increase SIRT6 deacetylation activity 35-fold at physiological concentrations (39).”
BackgroundCurrent Trends in Sirtuin Activator and Inhibitor Development
Bursch, K. L., Goetz, C. J., & Smith, B. C. (2024) · Molecules · doi:10.3390/molecules29051185 · Cited by 60
Reciprocal Regulation of Metabolic Reprogramming and Epigenetic Modifications in Cancer
Yu, X., Ma, R., Wu, Y., Zhai, Y., & Li, S. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00394 · Cited by 64
“Fatty acids are also a bona fide source of carbon for histone acetylation, contributing up to 90% of certain histone acetylation markers, i.e., H3K9ac, in immortalized hepatocytes (McDonnell et al., 2016).”
BackgroundKrautkramer, K. A., Dhillon, R. S., Denu, J. M., & Carey, H. V. (2017) · Translational research · doi:10.1016/j.trsl.2017.08.005 · Cited by 61
Self-citationMolecular and cellular regulatory roles of sirtuin protein
Pande, S., & Raisuddin, S. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2070722 · Cited by 58
“…have identified that the deacetylase activity of SIRT6 relies on the presence of free fatty acids and the presence of free fatty acids (myristic acid, oleic acid, and linoleic acid) the affinity of SIRT6 for an acetylated substrate had amplified up to 35 times (Feldman, Baeza, and Denu 2013).”
BackgroundStructural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation
Wang, Z. A., Markert, J. W., Whedon, S. D., Abeywardana, M. Y., Lee, K., Jiang, H., Suarez, C., Lin, H., Farnung, L., & Cole, P. A. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c13512 · Cited by 56
Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy
Chen, C., Wang, Z., & Qin, Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.935536 · Cited by 62
Sirtuin Modulators: Past, Present, and Future Perspectives
Fiorentino, F., Mautone, N., Menna, M., D’Acunzo, F., Mai, A., & Rotili, D. (2022) · Future Medicinal Chemistry · doi:10.4155/fmc-2022-0031 · Cited by 57
Miteva, Y., & Cristea, I. M. (2013) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.032847 · Cited by 58
“tions in the hydrolysis of long-chain fatty acyl groups (33, 34),”
BackgroundSirtuins 1 and 2 Are Universal Histone Deacetylases
Hsu, W. W., Wu, B., & Liu, W. R. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b00886 · Cited by 56
Sirt6 regulates lifespan in Drosophila melanogaster
Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S. J., Liu, J., Finn, M., Gordon, S., Zingas, L., Chang, C.-Y., Klein, M. A., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111176119 · Cited by 56
“This discrepancy may be explained by the finding that Sirt6 deacetylase activity is enhanced by binding to free fatty acids (13), as well as association with nucleosomes (12).”
BackgroundSelf-citationA Novel Continuous Assay for the Deacylase Sirtuin 5 and Other Deacetylases
Roessler, C., Tüting, C., Meleshin, M., Steegborn, C., & Schutkowski, M. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00293 · Cited by 58
Chemical reporters for exploring protein acylation
Thinon, E., & Hang, H. C. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150004 · Cited by 56
“Moreover, stereate (C18) and oleic acid (C18:1) were also reported to modify Cys [57] and Lys residues [25].”
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Nielsen, A. L., Rajabi, N., Kudo, N., Lundø, K., Moreno–Yruela, C., Bæk, M., Fontenas, M., Lucidi, A., Madsen, A. S., Yoshida, M., et al. (2021) · RSC Chemical Biology · doi:10.1039/d0cb00036a · Cited by 54
A Molecular Perspective on Sirtuin Activity
Teixeira, C. S. S., Cerqueira, N. M. F. S. A., Gomes, P., & Sousa, S. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228609 · Cited by 57
Chemical Probes Reveal Sirt2’s New Function as a Robust “Eraser” of Lysine Lipoylation
Xie, Y., Chen, L., Wang, R. Y., Wang, J., Li, J., Xu, W., Li, Y., Yao, S. Q., Zhang, L. N., Hao, Q., et al. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b06913 · Cited by 55
The Function and related Diseases of Protein Crotonylation
Wang, S., Mu, G., Qiu, B., Wang, M., Yu, Z., Wang, W., Wang, J., & Yang, Y. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.58872 · Cited by 53
“Afterwards, SIRT1, SIRT2 and SIRT3 were indicated to act as histone decrotonylases in vitro [28, 29].”
BackgroundPosttranslational modification of Sirt6 activity by peroxynitrite
Hu, S., Liu, H., Ha, Y., Luo, X., Motamedi, M., Gupta, M. P., Ma, J., Tilton, R. G., & Zhang, W. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.11.011 · Cited by 54
“Recently, Sirt6 activity was shown to be positively regulated by binding to long-chain free fatty acids [9].”
Trichostatin A inhibits deacetylation of histone H3 and p53 by SIRT6
Wood, M., Rymarchyk, S., Zheng, S. G., & Cen, Y. (2017) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2017.12.009 · Cited by 59
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The Mystery of Extramitochondrial Proteins Lysine Succinylation
Chinopoulos, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116085 · Cited by 55
“Sirtuins exhibit partially overlapping, but distinct deacylase activities [77].”
BackgroundA continuous, fluorogenic sirtuin 2 deacylase assay: substrate screening and inhibitor evaluation
Galleano, I., Schiedel, M., Jung, M., Madsen, A. S., & Olsen, C. A. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01532 · Cited by 53
NAD+ metabolism-based immunoregulation and therapeutic potential
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New assays and approaches for discovery and design of Sirtuin modulators
Schutkowski, M., Fischer, F. F., Roessler, C., & Steegborn, C. (2014) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2014.875526 · Cited by 53
“Significant depropionylation activity was also reported for Sirt1 [96], and more recently for Sirt2 [66], and propionylation appears to be a common modification in histones [97].”
BackgroundInfluentialInsights into Lysine Deacetylation of Natively Folded Substrate Proteins by Sirtuins
Knyphausen, P., de Boor, S., Kuhlmann, N., Scislowski, L., Extra, A., Baldus, L., Schacherl, M., Baumann, U., Neundorf, I., & Lammers, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.726307 · Cited by 52
“The other sirtuins have preferences for longer acyl chains (56, 57).”
BackgroundDeacylation Mechanism by SIRT2 Revealed in the 1′-SH-2′-O-Myristoyl Intermediate Structure
Wang, Y., Fung, Y. M. E., Zhang, W., He, B., Chung, M. W. H., Jin, J., Hu, J., Lin, H., & Hao, Q. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.02.007 · Cited by 52
Targeting Sirtuins: Substrate Specificity and Inhibitor Design
Rajabi, N., Galleano, I., Madsen, A. S., & Olsen, C. A. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.003 · Cited by 52
Sirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer
Huang, G., & Zhu, G. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s157724 · Cited by 53
“6 For example, SIRT1–3 and SIRT7 are primarily lysine deacetylases, 7,8 SIRT4 serves as both an ADP-ribosyl-transferase and lysine deacylase, 9,10 SIRT5 serves as a lysine demalonylase, 11 desuccinylase, 12 and deglutarylase, 13 and SIRT6 is an ADP-ribose transferase and deacetylase.”
The mechanisms, regulations, and functions of histone lysine crotonylation
Xie, J., Ju, J., Zhou, P., Chen, H., Wang, S., Wang, K., Wang, T., Chen, Y.-C., Chen, Y.-C., & Wang, K. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01830-w · Cited by 55
“Crotonyl group and lipoic acid modi fi cation are long-chain acylation modi fi cations, which are deacylated by decroto-nylases SIRT1, SIRT2, and SIRT1, SIRT2, SIRT3, and SIRT4 respectively [22].”
BackgroundThe Identification of a SIRT6 Activator from Brown Algae Fucus distichus
Rahnasto‐Rilla, M., McLoughlin, P., Kulikowicz, T., Doyle, M. E., Bohr, V. A., Lahtela-Kakkonen, M. K., Ferrucci, L., Hayes, M., & Moaddel, R. (2017) · Marine Drugs · doi:10.3390/md15060190 · Cited by 51
“Some compounds that enhance SIRT6 activity have been identified, including fatty acids and endogenous fatty acid ethanolamides [12,13].”
BackgroundHarlan, B. A., Pehar, M., Killoy, K. M., & Vargas, M. R. (2019) · The FASEB Journal · doi:10.1096/fj.201802752r · Cited by 50
Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease
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Mechanism of activation for the sirtuin 6 protein deacylase
Klein, M. A., Liu, C., Kuznetsov, V. I., Feltenberger, J. B., Tang, W., & Denu, J. M. (2020) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)49896-6 · Cited by 51
Self-citationLipid Metabolism and Epigenetics Crosstalk in Prostate Cancer
Pardo, J. C. T., de Porras, V. R., Gil, J., Pous, A. F., Puig‐Domingo, M., & Jordà, M. (2022) · Nutrients · doi:10.3390/nu14040851 · Cited by 55
Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5
Suenkel, B., Valente, S., Zwergel, C., Weiss, S., Bello, E. D., Fioravanti, R., Aventaggiato, M., Amorim, J. A., Garg, N., Kumar, S., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01215 · Cited by 49
Targeting aberrant cancer metabolism – The role of sirtuins
Kleszcz, R., Paluszczak, J., & Baer‐Dubowska, W. (2015) · Pharmacological Reports · doi:10.1016/j.pharep.2015.03.021 · Cited by 51
N‐Acylethanolamines Bind to SIRT6
Rahnasto‐Rilla, M., Kokkola, T., Jarho, E. M., Lahtela-Kakkonen, M. K., & Moaddel, R. (2015) · ChemBioChem · doi:10.1002/cbic.201500482 · Cited by 47
You, W., & Steegborn, C. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01455 · Cited by 45
Rumpf, T., Gerhardt, S., Einsle, O., & Jung, M. (2015) · Acta Crystallographica Section F Structural Biology Communications · doi:10.1107/s2053230x15019986 · Cited by 44
“Originally thought to function only as lysine deacetylases, it was recently reported that sirtuins are also able to cleave off other acyl groups (Feldman et al., 2013).”
BackgroundRuan, Q., Ruan, J., Zhang, W., Qian, F., & Yu, Z. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.08.010 · Cited by 44
Regulatory Effects of NAD + Metabolic Pathways on Sirtuin Activity
Zhang, N., & Sauve, A. A. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.012 · Cited by 46
SIRT2 and Lysine Fatty Acylation Regulate the Activity of RalB and Cell Migration
Spiegelman, N. A., Zhang, X., Jing, H., Cao, J., Kotliar, I. B., Aramsangtienchai, P., Wang, M., Tong, Z., Rosch, K. M., & Lin, H. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00492 · Cited by 43
Role of Sirtuins in Tumor Angiogenesis
Edatt, L., Poyyakkara, A., Raji, G. R., Ramachandran, V., Shankar, S. S., & Kumar, V. B. S. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01516 · Cited by 43
“In contrast to other KDACs, whose only function include deacetylation (31), sirtuins can also remove other groups like glutaryl (32), crotonyl (33), succinyl (34), palmitoyl (35), and myristoyl (36) groups.”
BackgroundEmerging roles of non-histone protein crotonylation in biomedicine
Hou, J., Zhou, L., Li, J., Wang, D., & Cao, J. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00616-2 · Cited by 44
“When cell energy is exhausted, peroxisomal fatty acid β-oxidation and H3K9 crotonylation increase and is accompanied by a decrease in the levels of ATP and acetyl-CoA, as well as a decrease in the expression of ribosomal biogenic genes [108].”
InfluentialThe Many Faces of Sirtuins: Sirtuins and the Warburg effect
Guarente, L. (2014) · Nature Medicine · doi:10.1038/nm.3438 · Cited by 43
Shaw, E., Talwadekar, M., Rashida, Z., Mohan, N., Acharya, A., Khatri, S., Laxman, S., & Kolthur‐Seetharam, U. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00212-19 · Cited by 42
“Although reports have shown that it has ADP-ribosyltransferase (21, 22) and NAD -dependent deacylase activities (23, 24), the robust catalytic activity, as well as the biological functions, of SIRT4 is largely unknown.”
BackgroundYu, T., Fan, K., Özata, D. M., Zhang, G., Fu, Y., Theurkauf, W. E., Zamore, P. D., & Weng, Z. (2021) · Nature Communications · doi:10.1038/s41467-020-20345-3 · Cited by 42
Preyat, N., Rossi, M., Kers, J., Chen, L., Bertin, J., Gough, P. J., Moine, A. L., Rongvaux, A., Gool, F. V., & Léo, O. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.60 · Cited by 42
A continuous sirtuin activity assay without any coupling to enzymatic or chemical reactions
Schuster, S., Roessler, C., Meleshin, M., Zimmermann, P., Simic, Z., Kambach, C., Schiene‐Fischer, C., Steegborn, C., Hottiger, M. O., & Schutkowski, M. (2016) · Scientific Reports · doi:10.1038/srep22643 · Cited by 42
Potent and Selective Inhibitors of Human Sirtuin 5
Kalbas, D., Liebscher, S., Nowak, T., Meleshin, M., Pannek, M., Popp, C., Alhalabi, Z., Bordusa, F., Sippl, W., Steegborn, C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01648 · Cited by 42
Guetschow, E. D., Kumar, S., Lombard, D. B., & Kennedy, R. T. (2015) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-015-9206-0 · Cited by 42
“Recent research has revealed novel catalytic functions for sirtuins, such as deacylation [3, 4], desuccinylation [5–8], deglutarylat ion [9], demalonylat ion [7, 10], and decrotonylation [11], with SIRT5 preferentially targeting succinyl, glutaryl, and malonyl moieties [5–10, 12].”
Chemical and Physiological Features of Mitochondrial Acylation
Ringel, A. E., Tucker, S. A., & Haigis, M. C. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.023 · Cited by 43
“Interestingly, the nuclear sirtuin, SIRT6, also contains a hydrophobic channel, and its deacetylase activity is potently stimulated by free fatty acids in vitro (Feldman et al., 2013).”
BackgroundChen, X., Sun, W., Huang, S., Zhang, H., Lin, G., Li, H., Qiao, J., Li, L., & Yang, S. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01183 · Cited by 40
Moghadam, B. H., Eskandari, M., Golestani, F., rezaee, S., Mahmoudi, N., & Gaeini, A. A. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.111090 · Cited by 42
Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations
Cercillieux, A., Ciarlo, E., & Cantó, C. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04499-5 · Cited by 42
“The strength of their deacylase activity and their preferred carbon chain lengths can also differ among the 7 family members [22].”
BackgroundMonounsaturated Fatty Acids: Key Regulators of Cell Viability and Intracellular Signaling in Cancer
Scott, J. S., Nassar, Z. D., Swinnen, J. V., & Butler, L. M. (2022) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-21-1069 · Cited by 42
SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation
Zhao, G., Wang, H., Xu, C., Wang, P., Chen, J., Wang, P., Sun, Z., Su, Y., Wang, Z., Han, L., et al. (2016) · Aging · doi:10.18632/aging.101038 · Cited by 41
“displays deacylase and ADP-ribosyltransferase activities [9, 10].”
Novel thiourea-based sirtuin inhibitory warheads
Zang, W., Hao, Y., Wang, Z., & Zheng, W. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.05.058 · Cited by 41
Zhang, N., Song, L., Xu, Y., Pei, X.-Y., Luisi, B. F., & Liang, W. (2021) · eLife · doi:10.7554/elife.75583 · Cited by 40
“Previous studies have identified mammalian histone deacetylase SIRT1 as being responsible for the removal of crotonylation in the nucleus (Bao et al., 2014; Feldman et al., 2013).”
BackgroundThe Double-Edged Sword of SIRT3 in Cancer and Its Therapeutic Applications
Ouyang, S., Zhang, Q., Lou, L., Zhu, K., Li, Z., Liu, P., & Zhang, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.871560 · Cited by 39
“These include myristoyl, palmitoyl, and others (Feldman et al., 2013).”
The role of mammalian sirtuins in cancer metabolism
Sebastián, C., & Mostoslavsky, R. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.07.008 · Cited by 39
Calorie restriction and NAD+/sirtuin counteract the hallmarks of aging
Michán, S. (2014) · Frontiers in bioscience · doi:10.2741/4283 · Cited by 40
“The latter enzymatic activity may include the removal of different acyl moieties of various carbon length, saturation, and chemical composition, such as acetyl, succinyl, malonyl, crotonyl, myristoyl, palmitoyl and lipoyl (176).”
BackgroundChemical Protein Degradation Approach and its Application to Epigenetic Targets
Itoh, Y. (2018) · The Chemical Record · doi:10.1002/tcr.201800032 · Cited by 41
Rajabi, N., Hansen, T. N., Nielsen, A. L., Nguyen, H. T., Bæk, M., Bolding, J. E., Bahlke, O. Ø., Petersen, S. E. G., Bartling, C. R. O., Strømgaard, K., et al. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202115805 · Cited by 37
Crotonylation and disease: Current progress and future perspectives
Yang, P., Qin, Y., Zeng, L., He, Y., Xie, Y., Cheng, X., Huang, W. G., & Cao, L. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115108 · Cited by 42
Spinelli, M., Fusco, S., & Grassi, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123820 · Cited by 41
“Recently, it has been demonstrated that sirtuins, which are members of a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, catalyze the hydrolysis of long-chain fatty acyl groups from the lysine residues of proteins [82,83].”
BackgroundEmerging Roles of Vitamin B12 in Aging and Inflammation
Simonenko, S. Y., Bogdanova, D. A., & Kuldyushev, N. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25095044 · Cited by 41
“The strongest deacetylase activity is observed for sirtuins 1–3 [97].”
BackgroundCoupling circadian rhythms of metabolism and chromatin remodelling
Masri, S., Orozco-Solís, R., Aguilar‐Arnal, L., Cervantes, M., & Sassone‐Corsi, P. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12509 · Cited by 38
“In this respect it is noteworthy that SIRT6 activity controls not only NAD+, but also fatty acids [64].”
BackgroundLysine Fatty Acylation: Regulatory Enzymes, Research Tools, and Biological Function
Komaniecki, G., & Lin, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.717503 · Cited by 37
“Unlike SIRT6, SIRT2 has strong in vitro deacetylase activity and has a plethora of reported deacetylase targets (Feldman et al., 2013; Wang et al., 2019).”
BackgroundMethodInfluentialHannoush, R. N. (2015) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2015.05.025 · Cited by 36
Pyridine Dinucleotides from Molecules to Man
Fessel, J. P., & Oldham, W. M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7120 · Cited by 35
“SIRT6, in addition to its deacetylase activity, has also been shown to possess a deacylase activity with particular affinity for removing long-chain acyl modifications from proteins and modulating cellular secretory activities (57, 110, 278).”
Mechanism of activation for the sirtuin 6 protein deacylase
Klein, M. A., Liu, C., Kuznetsov, V. I., Feltenberger, J. B., Tang, W., & Denu, J. M. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011285 · Cited by 37
“7-fold activation, consistent with previous reports under the same conditions (19).”
BackgroundResultInfluentialSelf-citationHepatic rRNA Transcription Regulates High-Fat-Diet-Induced Obesity
Oie, S., Matsuzaki, K., Yokoyama, W., Tokunaga, S., Waku, T., Han, S., Iwasaki, N., Mikogai, A., Yasuzawa-Tanaka, K., Kishimoto, H., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.03.038 · Cited by 39
“In contrast, deacylase activity of the Sirt family is also induced by fatty acids (Feldman et al., 2013).”
BackgroundChen, H., Wang, X.-C., Hou, H., Wang, J., Yang, Q., Chen, Y.-L., Chen, H., & He, G. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.125151 · Cited by 35
A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance
Das, C., Bhattacharya, A., Adhikari, S., Mondal, A., Mondal, P., Adhikary, S., Roy, S., Ramos, K. S., Yadav, K. K., Tainer, J. A., et al. (2024) · Oncogene · doi:10.1038/s41388-024-03054-9 · Cited by 39
“Nicotinamide, a well-known sirtuin inhibitor, thus assists in targeting cancer cell metabolism [182].”
BackgroundSIRT4 Is a Regulator of Insulin Secretion
Zaganjor, E., Vyas, S., & Haigis, M. C. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.06.002 · Cited by 35
Structure‐based discovery of new selective small‐molecule sirtuin 5 inhibitors
Liu, S., Ji, S., Yu, Z., Wang, H., Cheng, X., Li, W., Li, J., Yu, Y., Chen, Q., Yang, L., et al. (2017) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13077 · Cited by 34
Sirtuin 6, a possible therapeutic target for type 2 diabetes
Bae, E. J. (2017) · Archives of Pharmacal Research · doi:10.1007/s12272-017-0989-8 · Cited by 36
Swyter, S., Schiedel, M., Monaldi, D., Szunyogh, S., Lehotzky, A., Rumpf, T., Ovádi, J., Sippl, W., & Jung, M. (2018) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2017.0083 · Cited by 34
Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle
Hu, S.-H., Feng, Y.-Y., Yang, Y.-X., Ma, H., Zhou, S.-X., Qiao, Y.-N., Zhang, K.-H., Zhang, L., Huang, L., Yuan, Y., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00784-0 · Cited by 40
Recent Advances in Inhibitors of Sirtuin1/2: An Update and Perspective
Zhou, Z., Ma, T., Zhu, Q., Xu, Y., & Zha, X. (2018) · Future Medicinal Chemistry · doi:10.4155/fmc-2017-0207 · Cited by 34
Sirtuin 6 is a histone delactylase
Nickel, G. A., Pederson, N. J., Faheem, F., Yang, Z., Bulf, J., & Diehl, K. L. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110795 · Cited by 37
“We treated the WT and S6KO U2OS cells with sodium L-lactate and with panobinostat, a nonselective inhibitor of the Zn 2+ -dependent HDACs (Classes I, II, IV) and again measured global histone acetylation and lactylation levels with the pan-antibodies (Fig.”
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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