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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
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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).”
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BackgroundSIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
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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
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“SAHA (1) Romidepsin (2) Panobinostat (5) Belinostat (3) HN O H N”
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Aramsangtienchai, P., Spiegelman, N. A., He, B., Miller, S. P., Dai, L., Zhao, Y., & Lin, H. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00396 · Cited by 118
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“Indeed, SIRT5 functions as desuccinylase or demalonylase [18], whereas SIRT6 functions as demyristoylase [2, 19].”
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Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH
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“In contrast to a previous report (37), on the other hand, we did not observe significant levels of deacylation against any substrates by SIRT4, SIRT5, or SIRT7.”
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“Recently, long-chain N-acylation on lysine residues has also been shown to be reversible (with members of the sirtuin family catalyzing the deacylation reaction), and thus to have the potential of dynamically regulate protein properties (Feldman et al. 2013; Bheda et al. 2016; Jing et al. 2017).”
BackgroundSIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix
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Sirtuin 6: linking longevity with genome and epigenome stability
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The Regulation and Function of Histone Crotonylation
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“A comprehensive analysis of the activity of the seven mammalian sirtuins using H3 peptides carrying diverse acyl groups on Lys 9, revealed HDCR activity for Sirt1 and Sirt2 (Feldman et al., 2013).”
BackgroundSIRT7 Is an RNA-Activated Protein Lysine Deacylase
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“For example, long-chain fatty acids activate the deacetylase function of SIRT6, and this may affect histone acetylation [47, 48].”
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“The fi gure illustrates the timeline of protein lipidation research from their origin to the most advanced scienti fi c discoveries, including regulatory enzymes, important protein substrates, clinical trials and the development of inhibitors autopalmitoylation of DHHC13, 17, 19 and 22 was not detectable by tritiated pa…”
BackgroundInfluentialMetabolism and the Epigenome: A Dynamic Relationship
Haws, S. A., Leech, C. M., & Denu, J. M. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.04.002 · Cited by 112
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“Furthermore, diverse catalytic activities have been uncovered for sirtuins, including, but not limited to, depropionylation, debutyrylation, desuccinylation, and de-fatty acylation (Du et al., 2011; Feldman et al., 2013; Jiang et al., 2013; Anderson et al., 2017).”
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Chemical and structural biology of protein lysine deacetylases
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The Chemical Reactivity of Membrane Lipids
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Protein S-palmitoylation and cancer
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Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens
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“For example, humanSIRT1,aclass I sirtuin, ismostefficient atdeacetylation,whereasSIRT5, belonging to class III, hashighest activity toward succinylation (Du et al., 2011; Feldman et al., 2013).”
BackgroundAminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure–Activity Relationship Study
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“Moreover, our study reveals the first lysine defatty-acylation substrate for SIRT2 and uncovers the physiological relevance of SIRT2 as a lysine defatty-acylase (Feldman et al., 2013; Liu et al., 2015; Teng et al., 2015).”
BackgroundInfluentialStructural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives
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“Subsequently, a wide range of sirtuins was shown to have long chain N-acyllysine deacylating activity in an isolated enzyme system [22,23].”
BackgroundKollenstart, L., de Groot, A. J. L., Janssen, G. M. C., Cheng, X., Vreeken, K., Martino, F., Côté, J., van Veelen, P. A., & van Attikum, H. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010302 · Cited by 95
Exploring the emerging complexity in transcriptional regulation of energy homeostasis
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“SIRT1–3, histone deacetylases, can remove the propionyl and butyryl groups from lysine residues in the presence of NAD+ [153, 156, 159].”
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“FFAs (myristic, oleic, or linoleic acid) induce a 35-fold increase in SIRT6 catalytic activity but do not affect the activity of SIRT1 (64).”
BackgroundIdentifying the functional contribution of the defatty-acylase activity of SIRT6
Zhang, X., Khan, S., Jiang, H. X., Antonyak, M. A., Chen, X., Spiegelman, N. A., Shrimp, J. H., Cerione, R. A., & Lin, H. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2106 · Cited by 91
“There are three reported enzymatic activities of SIRT6: deacetylation 3,10–12 , defatty-acylation 13,14 , and mono-adenosine diphosphate (ADP)- Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the…”
InfluentialSIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
Du, Y., Hu, H., Qu, S., Wang, J., Hua, C., Zhang, J., Wei, P., He, X., Hao, J., Liu, P., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.037 · Cited by 87
“SIRT6 possesses many enzymatic activities including ADP-ribosyltransferase [5], deacetylase [6], and long-chain deacylase [7,8].”
BackgroundNon-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1
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Chiral Posttranslational Modification to Lysine ε-Amino Groups
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Who watches the watchmen? Regulation of the expression and activity of sirtuins
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“Given that enzymatic activity of this sirtuin is increased by fatty acids (132), this fact raises an intriguing possibility of SIRT6 providing a molecular brake on HIF-1a-mediated repression of SIRT2 in situations of nutrient excess.”
BackgroundSirtuins and the Metabolic Hurdles in Cancer
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“SIRT6 activity in vitro is induced by fatty acids [25].”
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Diverse Activities of Histone Acylations Connect Metabolism to Chromatin Function
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“Also, only HDAC3 (Madsen and Olsen, 2012), Sirt1, Sirt2, and Sirt3 (Bao et al., 2014; Feldman et al., 2013) have been shown to decrotonylate histones.”
Identification of and molecular basis for sirt6 loss-of-function point mutations in cancer
Kugel, S., Feldman, J. L., Klein, M. A., Silberman, D. M., Sebastián, C., Mermel, C., Dobersch, S., Clark, A. R., Getz, G., Denu, J. M., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.09.022 · Cited by 81
“…reactions were analyzed by reversed phase high-performance liquid chromatography on Kinetex C18 column (100 Å; 100 3 4.6 mm; 2.6 mm; Phenomenex) by monitoring the formation of the deacylated product at 214 nm (Feldman et al., 2013) and also described in Supplemental Experimental Procedures.”
InfluentialAberrant protein acylation is a common observation in inborn errors of acyl-CoA metabolism
Pougovkina, O., te Brinke, H., Wanders, R. J. A., Houten, S. M., & de Boer, V. C. J. (2014) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-014-9684-9 · Cited by 80
“Lysine acylation can be counteracted by sirtuins, which were recently shown to deacylate a wide range of lysine acylations, from acetylated lysines up to palmitoylated lysines (Feldman et al 2013) in a NAD+ dependent manner (Haigis and Sinclair 2010).”
Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators
Klein, M. A., & Denu, J. M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.011438 · Cited by 87
“5 mM), as more potent activators, albeit with lowermaximum -fold activation of SIRT6, than their fatty acid cousins, oleic and myristic acid (EC50 of 90 and 246mM) (25, 148).”
BackgroundInfluentialSelf-citationNúñez‐Álvarez, Y., & Suelves, M. (2021) · FEBS Journal · doi:10.1111/febs.15895 · Cited by 85
Rogina, B., & Tissenbaum, H. A. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1393181 · Cited by 93
“…of signaling molecules including decrotonylation, ADP-ribosylation, diacylation, desuccinylation, demalonylation, depropynylation, delipoamidation, and deglutarylation, and other long-chain fatty acid deacylations (Feldman, Baeza, and Denu, 2013; Choudhary et al., 2014; Fiorentino et al., 2022).”
BackgroundGuan, X., Lin, P. C., Knoll, E., & Chakrabarti, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107729 · Cited by 87
Zwaans, B. M. M., & Lombard, D. B. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.016287 · Cited by 81
“Some sirtuins remove noncanonical lysine post-translational modifications such as succinyl, malonyl, glutaryl and acyl groups (Du et al., 2011; Feldman et al., 2013; Jiang et al., 2013; Peng et al., 2011; Tan et al., 2014).”
BackgroundStructure‐Based Development of an Affinity Probe for Sirtuin 2
Schiedel, M., Rumpf, T., Karaman, B., Lehotzky, A., Gerhardt, S., Ovádi, J., Sippl, W., Einsle, O., & Jung, M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201509843 · Cited by 79
Betsinger, C. N., & Cristea, I. M. (2019) · Journal of Proteome Research · doi:10.1021/acs.jproteome.9b00086 · Cited by 84
Roessler, C., Nowak, T., Pannek, M., Gertz, M., Nguyen, G. T. T., Scharfe, M., Born, I., Sippl, W., Steegborn, C., & Schutkowski, M. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201402679 · Cited by 79
NAD Biosynthesis in Humans - Enzymes, Metabolites and Therapeutic Aspects
Dölle, C., Skoge, R. H., VanLinden, M. R., & Ziegler, M. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/15680266113136660206 · Cited by 80
The Two-Faced Role of SIRT6 in Cancer
Fiorentino, F., Carafa, V., Favale, G., Altucci, L., Mai, A., & Rotili, D. (2021) · Cancers · doi:10.3390/cancers13051156 · Cited by 79
“The unsaturated 18-carbons FFAs oleic (1b) and linoleic acid (1c) (Figure 2) displayed EC50 values of 90 µM and 100 µM, yielding up to 5.8 and 6.8 times SIRT6 maximum activation, respectively [11].”
BackgroundInfluentialAn Expanding Repertoire of Protein Acylations
Xu, Y., Shi, Z., & Bao, L. (2022) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2022.100193 · Cited by 80
“Shortly after the first discovery of Kpr and Kbu, several SIRT enzymes, including SIRT1/2/3 (69, 70), were also proved to have lower depropionylase, debutyrylase, and decrotonylase activities in addition to their deacetylase activities.”
BackgroundTao, J., Zhang, J., Ling, Y., McCall, C. E., & Liu, T. F. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00419 · Cited by 77
Sirtuin family in autoimmune diseases
Tao, Z., Jin, Z., Wu, J., Cai, G., & Yu, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1186231 · Cited by 79
Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration
Pehar, M., Harlan, B. A., Killoy, K. M., & Vargas, M. R. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7145 · Cited by 77
“SIRT6 and SIRT7 display weak deacetylase activity in vitro and instead, SIRT6 can catalyze ADP-ribosylation and lysine defatty acylation (56, 80, 93), while SIRT7 function as an NAD + -dependent histone desuccinylase (92).”
Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model
Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201601294r · Cited by 76
“Sirt1; (11)] and/or the strong deacetylase activity of Sirt1 and -2 in comparisonwith the weak deacetylase activity of Sirt6, which could have prevented compound 1 from effectively blocking Sirt1/2 in our model (19).”
BackgroundRajabi, N., Auth, M., Troelsen, K. R., Pannek, M., Bhatt, D. P., Fontenas, M., Hirschey, M. D., Steegborn, C., Madsen, A. S., & Olsen, C. A. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201709050 · Cited by 76
Proteomic analysis of fatty-acylated proteins
Peng, T., Thinon, E., & Hang, H. C. (2015) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2015.11.008 · Cited by 77
Mellini, P., Itoh, Y., Tsumoto, H., Li, Y., SUZUKI, M. T., Tokuda, N., Kakizawa, T., Miura, Y., Takeuchi, J., Lahtela-Kakkonen, M. K., et al. (2017) · Chemical Science · doi:10.1039/c7sc02738a · Cited by 76
SIRT7 Is Activated by DNA and Deacetylates Histone H3 in the Chromatin Context
Tong, Z., Wang, Y., Zhang, X., Kim, D. D., Sadhukhan, S., Hao, Q., & Lin, H. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b01084 · Cited by 75
“The open reading frames of full length human SIRT7 (1-400), ΔN (56-400), ΔC (1-364), and the core domain (56-364) were inserted into the pET28a vector.”
MethodFruscia, P. D., Zacharioudakis, E., Liu, C., Moniot, S., Laohasinnarong, S., Khongkow, M., Harrison, I. F., Koltsida, K., Reynolds, C. R., Schmidtkunz, K., et al. (2014) · ChemMedChem · doi:10.1002/cmdc.201402431 · Cited by 73
Histone Acylation beyond Acetylation: Terra Incognita in Chromatin Biology.
Rousseaux, S., & Khochbin, S. (2015) · PubMed · doi:10.22074/cellj.2015.506 · Cited by 74
“Additional investigations revealed that HDAC3 (18) and Sirt1 and Sirt2 (19) could decrotonylate histone peptides in vitro to some extent.”
Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells
Xiong, X., Wang, G., Tao, R., Wu, P., Kono, T., Li, K., Ding, W., Tong, X., Tersey, S. A., Harris, R. A., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3778-2 · Cited by 74
“SIRT6 can also remove long-chain fatty acyl groups from lysine residues of its substrates such as TNF-α [10, 11].”
Thiomyristoyl peptides as cell-permeable Sirt6 inhibitors
He, B., Hu, J., Zhang, X., & Lin, H. (2014) · Organic & Biomolecular Chemistry · doi:10.1039/c4ob00860j · Cited by 73
SIRT2 Reverses 4-Oxononanoyl Lysine Modification on Histones
Jin, J., He, B., Zhang, X., Lin, H., & Wang, Y. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b04977 · Cited by 73
Using mitochondrial sirtuins as drug targets: disease implications and available compounds
Gertz, M., & Steegborn, C. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2180-7 · Cited by 73
“For Sirt6, the identification of fatty acids as activators for its low basal deacetylation activity indicates that this isoform should also be amenable to small molecule activation (see [42] and below).”
BackgroundArachidonic and oleic acid exert distinct effects on the DNA methylome
Silva-Martínez, G. A., Rodríguez‐Ríos, D., Alvarado‐Caudillo, Y., Vaquero, A., Esteller, M., Carmona, F. J., Morán, S., Nielsen, F. C., Lindholm, M., Wróbel, K., et al. (2016) · Epigenetics · doi:10.1080/15592294.2016.1161873 · Cited by 74
“SIRT6 can also be activated by long-chain FAs, in particular OA, and contributes to regulation of b-oxidation.(71,72) However, knockdown of SIRT6 EPIGENETICS 329”
BackgroundChemical signaling between gut microbiota and host chromatin: What is your gut really saying?
Krautkramer, K. A., Rey, F. E., & Denu, J. M. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.761577 · Cited by 70
“More recently, the histone H3 Lys-9 and Lys-56 deacetylase Sirt6, which has inherently low deacetylase activity in vitro, was reported to be activated by long-chain free fatty acids (20); however, whether these long-chain free fatty acids have a role in vivo remains to be determined.”
BackgroundSelf-citationKhan, R. I., Nirzhor, S. S. R., & Akter, R. (2018) · Biomolecules · doi:10.3390/biom8030044 · Cited by 71
“Recently, it has been discovered that the free fatty acids (FFAs) endogenously activates SIRT6 deacetylase in vitro however, it still remains to be seen how it impacts the deacetylase activity in vivo [44-48].”
BackgroundUpdates on the epigenetic roles of sirtuins
Kosciuk, T., Wang, M., Hong, J. Y., & Lin, H. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.01.023 · Cited by 73
Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage
Shao, J., Yang, X. Y., Liu, T., Zhang, T., Xie, Q. R., & Xia, W. (2016) · Protein & Cell · doi:10.1007/s13238-016-0257-6 · Cited by 70
“SIRT6 is predominantly localized in the nucleus, functioning as an ADP-ribosyltransferase and NAD+-dependent deacetylase (Liszt et al., 2005; Michishita et al., 2008; Feldman et al., 2013).”
Chromatin dynamics and histone modifications in intestinal microbiota-host crosstalk
Fellows, R., & Varga‐Weisz, P. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.12.005 · Cited by 77
“riters,” acyltransferases, bound by “readers” for downstream events, and removed by ) [145,146], (f) [147], (g) [51,140,141], (h) [50,55,56,145,146], (i) [147], (j) [148,149], (k) .”
Reading the Combinatorial Histone Language
Su, Z., & Denu, J. M. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00864 · Cited by 82
Self-citationLoss of Fatty Acid Binding Protein 4/aP2 Reduces Macrophage Inflammation Through Activation of SIRT3
Xu, H., Hertzel, A. V., Steen, K. A., & Bernlohr, D. (2016) · Molecular Endocrinology · doi:10.1210/me.2015-1301 · Cited by 71
Shang, J., Ning, S., Chen, Y., Chen, T., & Zhang, J. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-0442-2 · Cited by 75
Protein Lipidation by Palmitoylation and Myristoylation in Cancer
Fhu, C. W., & Ali, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.673647 · Cited by 70
SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells
Sociali, G., Grozio, A., Caffa, I., Schuster, S., Becherini, P., Damonte, P., Sturla, L., Fresia, C., Passalacqua, M., Mazzola, F., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201800321r · Cited by 68
“Among other SIRT family members, SIRT6 is unique, being endowed with deacetylase activity, but also with a de-fatty acylase activity (17), and also with mono-ADPribosyltransferase activity (18, 19).”
BackgroundMetabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors
Montgomery, D. C., Sorum, A. W., Guasch, L., Nicklaus, M. C., & Meier, J. L. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.06.015 · Cited by 67
Costa‐Machado, L. F., & Fernández-Marcos, P. J. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1634953 · Cited by 66
“The activity of SIRT6 is closely linked to fatty acids in two ways: the presence of fatty acids was shown to induce SIRT6 otherwise weak deacetylase activity [211]; and SIRT6 has been shown to remove longchain fatty acids from other proteins, such as TNFα [211–213].”
BackgroundThe Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11
Madsen, A. S., Kristensen, H. M. E., Lanz, G., & Olsen, C. A. (2013) · ChemMedChem · doi:10.1002/cmdc.201300433 · Cited by 67
Molecular Pathways: Emerging Roles of Mammalian Sirtuin SIRT7 in Cancer
Paredes, S., Villanova, L., & Chua, K. F. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1547 · Cited by 65
Ketone bodies as epigenetic modifiers
Ruan, H., & Crawford, P. A. (2018) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000475 · Cited by 71
Yuan, H., Zhao, M., Zhao, L., Yun, H., Yang, G., Geng, Y., Wang, Y.-F., Zheng, W., Yuan, Y., Song, T., et al. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00841-y · Cited by 68
“Emerging evidence suggests that sirtuins can remove acyl groups in addition to acetyl groups from lysine residues [45, 46].”
BackgroundLiao, W., Xu, N., Zhang, H., Liao, W., Wang, Y., Wang, S., Zhang, S., Jiang, Y., Xie, W., & Zhang, Y. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.699 · Cited by 65
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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