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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).”
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“SIRT6 is one of seven members of the mammalian NAD dependent protein deacetylases that are evolutionarily ancient (1).”
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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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“For instance, omega-3 fatty acids, including eicosapentaenoic acid (20:5,n-3) and docosahexaenoic acid (22:6,n-3), are reported to exert beneficial effects against cardiovascular disease and inflammation (29, 30).”
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
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“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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“Readers are hereby redirected to other comprehensive reviews for further insights into AA network linkage to oxidative, inflammatory, respiratory, cardiovascular, neurodegenerative disorders as well as cancer and senescence (Aghasafari et al., 2019; Borin et al., 2017; Fan et al., 2016; Feldman et al., 2013; Guarner &…”
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Deciphering the Allosteric Activation Mechanism of SIRT6 Using Molecular Dynamics Simulations
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Mechanism-based enzyme activating compoundsPreprint
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“Moreover, SIRT1, SIRT2, and SIRT3 have all been shown to possess histone de-crotonylase activity in vitro (Feldman et al., 2013; Bao et al., 2014; Liao et al., 2023).”
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“Sirtuins are conserved across domains of life, maintaining cellular homeostasis through regulation of a diverse array of lysine acylations [229–231].”
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“SIRT6 ’ s relatively low activity on acetylated peptides (21, 23 – 25) has led to an idea that SIRT6 alone possesses insuf fi cient deacetylase activity (26, 27).”
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“This kind of diet decreases NAD+ levels due to reducing nicotinamide phosphoribosyl transferase expression [45] and diminishes acetyl-CoA content [46] while elevating long-chain free fatty acids that increase activation of the deacetylase activity of SIRT6 [47], which affects the circadian metabolic processes.”
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Sirtuin Activation by Small Molecules
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DNA stimulates SIRT6 to mono-ADP-ribosylate proteins within histidine repeatsPreprint
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Drugs Targeting Sirtuin 2 Exhibit Broad-Spectrum Anti-Infective Activity
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SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1
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“Besides major acetylase properties, SIRT6 has been reported to efficiently catalyze the fatty-acid deacylation and ADP-ribosyltransferase activities on substrates [34, 35].”
BackgroundGenetically encoding ε-N-methacryllysine into proteins in live cells
Zhu, T.-Y., Chen, S., Zhang, M., Li, H., Wu, T., Ajiboye, E. G., Wang, J. W., Jin, B., Liu, D., Zhou, X., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57969-2 · Cited by 3
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“Similar to previous observations (25), the human sirtuins displayed varied and differentiated zymographs (Fig.”
MethodResultInfluentialAssessment of SIRT2 Inhibitors in Mouse Models of Cancer
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“SIRT1 and SIRT2 were demonstrated to reduce H3K9cr levels in vitro through the use of radiometric thin-layer chromatography (Feldman et al. 2013).”
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“…to the SIRT6 deacetylase-selective activators MDL-800, 4H-chromen, and UBCS039 described above in Section 2.2 and depicted in Figure 3, several other SIRT6 deacetylase-selective activators (i.e., CL-5D (Klein et al., 2020), myristic acid (Feldman et al., 2013), and the nitrated linoleic acids 9-”
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“…modifications simultaneously, such as Gcn5 has the transferase activity of acetylation, crotonylation, and benzoylation (8, 33), and SIRT2 also has deacylation activity of acetylation, propiony lation, butyrylation, crotonylation, benzoylation, and methacryloylation (2, 5, 42–44).”
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“The seven mammalian sirtuins, homologues of yeast sir2 , are NAD + - dependent enzymes with catalytic activities mediating lysine deacetyl ation, deacylation, or monoADP ribosyltransferase activity (MADPR) ( 2 , 3 ).”
Histidine and tyrosine residues are targets for SIRT6 ADP-ribosylation activity
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“For example, some members (such as SIRT6) have evolved elongated hydrophobic pockets to accommodate long-chain fatty acids (Pan et al. 2011; Feldman et al. 2013), while others (like SIRT5) have incorporated positively charged regions to capture acidic acyl modifications (Du et al. 2011).”
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The Divergent 3D Genome Landscapes of Aging and Neurodegenerative mouse modelsPreprint
Kashuk, E., Smirnov, D., Eremenko, E., Tsitrina, A. A., Kriukov, D. V., Golova, A., Kaluski-Kopatch, S., Khrameeva, E. E., & Toiber, D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.10.687599 · Cited by 1
Mechanisms and Dynamics of Protein Acetylation in
Baeza, M., Smallegan, M. J., & Denu, J. M. (2016)
Self-citationLigand Binding and Catalysis in Selected Sirtuin Isozymes
Yu, J. (2016) · NDSU Repository (North Dakota State University)
A Role for Sirtuins in Maintaining Mammalian Lifespan and Healthspan
Giblin, W. (2017) · Deep Blue (University of Michigan)
Metabolic Dysregulation in Environmental Carcinogenesis and Toxicology
Robey, R. B. (2017) · John Wiley & Sons, Inc. eBooks · doi:10.1002/9781119023647.ch15
Chromatin and Nuclear Signaling
Angulo‐Ibáñez, M., & Chua, K. F. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813499-3.00010-1
Reactive Acyl-CoA Species and Deacylation by the Mitochondrial Sirtuins
Hershberger, K. A., & Hirschey, M. D. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813499-3.00007-1
Cyclic Peptide-Based Sirtuin Substrates
Chen, D., Yan, L., & Zheng, W. (2019) · Molecules · doi:10.3390/molecules24030424
“Since SIRT1/2/3 were also recently found to exhibit robust demyristoylase activity [26,31], it seemed plausible to construct another robust SIRT1/2/3 substrate by simply replacing the acetyl in Figure 3.”
BackgroundThe interplay between diet, epigenetics and the circadian clock
DiTacchio, L. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816843-1.00013-8
Yang, Y. J., & Sauve, A. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-409547-2.14664-5
Circadian Changes in Gut Peptide Levels and Obesity
Dailey, M. J., & Mahoney, M. M. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-816658-1.00003-x
The evolution of human SIRT1 for multi-specificity is enabled by active-site adaptationPreprint
Hendler‐Neumark, A., Akiva, E., Sandhu, M., Goldberg, D. T., Arbely, E., Jackson, C. J., & Aharoni, A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.12.903153
“In addition, other studies revealed that the substrate preference of sirtuins is not limited to acetyl-lysine residues but these enzymes, primarily SIRT6, can recognize different fatty-acid acyl-lysine modified substrates (Feldman et al., 2013; Jiang et al., 2013).”
BackgroundIto, A., & Yoshida, M. (2017) · Springer eBooks · doi:10.1007/978-4-431-56529-1_3
Sirtuin signaling in hematologic malignancies
Denu, R. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822467-0.00012-7
REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Reinke, H., & Asher, G. (2016)
Global Profiling of Lysine Crotonylation in Vascular Smooth Muscle Cell Phenotypic RemodelingPreprint
Cao, S., Yue, L., & Dong, L. (2021) · Research Square · doi:10.21203/rs.3.rs-504286/v1
Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine
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Ghosh, S. (2019) · Springer theses · doi:10.1007/978-981-32-9267-3_6
Rajabi, N., Nielsen, A. L., & Olsen, C. A. (2019) · ChemRxiv · doi:10.26434/chemrxiv.11339774 · Cited by 1
Kandror, K. V. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737160544.793572058
Doulias, P. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734925748.793578235
Wang, Z. A., Hsu, W. W., & Liu, W. R. (2017) · Springer eBooks · doi:10.1007/978-3-319-31143-2_1-1
Nakajima, T., & Fujita, H. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.733671993.793548965
Kapahi, P. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.735571855.793559381
Faculty Opinions recommendation of Mechanisms and dynamics of protein acetylation in mitochondria.
Ji, L. L. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.726108102.793564356
Development of Sirtuin Fluorescence Probes and Medicinal Chemistry Research Targeting SIRT Family
Kawaguchi, M., Nakajima, Y., & Nakagawa, H. (2022) · Journal of Synthetic Organic Chemistry Japan · doi:10.5059/yukigoseikyokaishi.80.831
Epigenetics of radiation-induced GI damage: Role of protein modifications
Gupta, N., Prakash, A., Agrawala, P. K., & Dwarakanath, B. S. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823931-5.00012-8
Colcerasa, A., Melesina, J., Moser, P., Vogelmann, A., Friedrich, F., Tzortzoglou, P., Neuwirt, E., Sum, M., Zhang, L., Ramos‐Morales, E., et al. (2023) · ChemRxiv · doi:10.26434/chemrxiv-2023-7x8pz
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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