The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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).”
BackgroundOmega-3 Fatty Acids and Inflammatory Processes
Calder, P. C. (2010) · Nutrients · doi:10.3390/nu2030355 · Cited by 1,116 · cited 1×
“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
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.”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Items 401–500 of 661
Probing Chromatin-modifying Enzymes with Chemical Tools
Fischle, W., & Schwarzer, D. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b01023 · Cited by 15
Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance
Gertman, O., Omer, D., Hendler‐Neumark, A., Stein, D., Onn, L., Khukhin, Y., Portillo, M., Zarivach, R., Cohen, H. Y., Toiber, D., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-21887-9 · Cited by 15
Sirtuin 6 is a regulator of dendrite morphogenesis in rat hippocampal neurons
Matsuno, H., Tsuchimine, S., Fukuzato, N., O'Hashi, K., Kunugi, H., & Sohya, K. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104959 · Cited by 15
Evaluation of acyllysine isostere interactions with the aromatic pocket of the AF9 YEATS domain
Travis, C. R., Francis, D. Y., Williams, D. C., & Waters, M. L. (2022) · Protein Science · doi:10.1002/pro.4533 · Cited by 14
“Adding to the value of this ligand in inhibitor design, the ethylcarbamoyl isostere of Kcr is resistant to removal by SIRT1, a key eraser protein reported to decrotonylate H3K9cr.(58,60) To this end, future work could explore development of GCE technology to incorporate ethoxycarbonyl or ethylcarbamoyl isosteres of Kc…”
BackgroundInfluentialStudies of the Binding of Modest Modulators of the Human Enzyme, Sirtuin 6, by STD NMR
Bolívar, B. E., & Welch, J. T. (2017) · ChemBioChem · doi:10.1002/cbic.201600655 · Cited by 15
Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin
You, W., & Steegborn, C. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00407 · Cited by 15
Metabolic Effects of Caloric Restriction
Lamming, D. W., & Anderson, R. M. (2014) · Wiley eBooks · doi:10.1002/9780470015902.a0021316.pub2 · Cited by 15
“The finding that SIRT6 deacetylase activity is greatly enhanced by fatty acids is a rather inter-estingdevelopmentthatsuggeststhatintracellularfreefattyacidscouldbeendogenousligandsforSIRT6(Feldman et al. , 2013).”
BackgroundJiang, L., Yin, X., Zhang, H., Zhang, X., Cao, Z., Zhou, M., & Xu, W. (2023) · BioMed Research International · doi:10.1155/2023/4444869 · Cited by 14
Continuous Fluorescent Sirtuin Activity Assay Based on Fatty Acylated Lysines
Zessin, M., Meleshin, M., Hilscher, S., Schiene‐Fischer, C., Bařinka, C., Jung, M., & Schutkowski, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087416 · Cited by 14
“Based on the observation that sirtuins are able to recognize fatty acyl chains [46], several direct and fluorescence-based activity assays have been developed [50,58,59].”
BackgroundMarmisolle, I., Chacón, E., Mansilla, S., Ruiz, S., Bresque, M., Martínez, J., Martínez‐Zamudio, R. I., Herbig, U., Liu, J., Finkel, T., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103606 · Cited by 15
“Long chain free fatty acids can increase SIRT6 catalytic activity [74], and these lipids are higher in senescent than control fibroblasts [13].”
Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer
Zhang, X., Dong, Z., & Cui, H. (2021) · Biomolecules · doi:10.3390/biom11101406 · Cited by 14
He, Y., Yan, L., Zang, W., & Zheng, W. (2015) · Organic & Biomolecular Chemistry · doi:10.1039/c5ob01721a · Cited by 14
Biochemical Analysis of Histone Succinylation
Yokoyama, A., Katsura, S., & Sugawara, A. (2017) · Biochemistry Research International · doi:10.1155/2017/8529404 · Cited by 15
“The identification of decrotonylation activity of Class I HDACs also supports the hypothesis that a histone deacetylase family protein could remove acyl moieties [28, 29].”
BackgroundCrotonylation modification and its role in diseases
Guo, Y., Li, J., & Zhang, K. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1492212 · Cited by 15
Structural basis for sirtuin 2 activity and modulation: Current state and opportunities
Bernhard, S. P., Ruiz, F. X., Remiszewski, S., Todd, M. J., Shenk, T. E., Kulp, J. L., & Chiang, L. W. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110274 · Cited by 13
“Given that other noncrystallized SIRT6 activators do work this way ( e.g. , CL5D (62) and palmitic acid (63)), it is plausible that the MDL derivatives, quercetin and UBCS039, can behave as activators of deacetylase activity and competitive inhibitors of demyr-istoylation and deacylation of other…”
Gut Microbiome, a Potent Modulator of Epigenetics in Human Diseases
Kim, J. (2017) · Journal of Bacteriology and Virology · doi:10.4167/jbv.2017.47.2.75 · Cited by 13
“한편, 히스톤 디아실화는 HDAC III 계열인 SIRTs 단백질 이 수행할 수 있는 것으로 밝혀져 있다 (22, 23).”
Effects of Dimerization on the Deacylase Activities of Human SIRT2
Yang, J., Nicely, N. I., & Weiser, B. P. (2023) · Biochemistry · doi:10.1021/acs.biochem.3c00381 · Cited by 12
Colcerasa, A., Friedrich, F., Melesina, J., Moser, P., Vogelmann, A., Tzortzoglou, P., Neuwirt, E., Sum, M., Robaa, D., Zhang, L., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00229 · Cited by 13
Substrate-Dependent Sensitivity of SIRT1 to Nicotinamide Inhibition
Rymarchyk, S., Kang, W., & Cen, Y. (2021) · Biomolecules · doi:10.3390/biom11020312 · Cited by 14
“to the deacetylase activity, SIRT1 also removes acyl groups from lysine residues [33,34], although the physiological relevance of these novel posttranslational modifications are yet to be established.”
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 · doi:10.1002/ange.201709050 · Cited by 14
Chemical Probes in Sirtuin Research
Hu, X., & Zheng, W. (2017) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.014 · Cited by 13
The Many Faces of Lipids in Genome Stability (and How to Unmask Them)
Moriel‐Carretero, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222312930 · Cited by 13
“Since, upon detection of long-chain fatty acids, SIRT6 catalysis is stimulated [58], it is both tempting and parsimonious, in order to explain all its aforementioned roles, to invoke its role as a “nuclear de-lipidation” cleaner whose activity keeps a healthy nuclear proteome.”
BackgroundPhotorespiration – Damage Repair Pathway of the Calvin–Benson Cycle
Bauwe, H. (2018) · Wiley eBooks · doi:10.1002/9781119312994.apr0552 · Cited by 13
Comment on ‘YcgC represents a new protein deacetylase family in prokaryotes’
Kremer, M., Kuhlmann, N., Lechner, M., Baldus, L., & Lammers, M. (2018) · eLife · doi:10.7554/elife.37798 · Cited by 13
Epigenetic meets metabolism: novel vulnerabilities to fight cancer
Scumaci, D., & Zheng, Q. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01253-7 · Cited by 13
“The removal of acylation groups is specifically ascribed to peculiar histone deacetylase (HDAC): sirtuin-family HDACs exert their activity on succinyl, malonyl and glutaryl groups [24–26].”
BackgroundInfluentialDiscovery of De Novo Macrocycle Inhibitors of Histone Deacetylase 11
Danková, D., Nielsen, A. L., Zarda, A., Hansen, T. N., Hesse, M., Benová, M., Tsiris, A., Bartling, C. R. O., Will, E. J., Strømgaard, K., et al. (2025) · JACS Au · doi:10.1021/jacsau.4c01148 · Cited by 13
Structural and enzymatic plasticity of SIRT6 deacylase activity
Wang, Z. A., Markert, J. W., Whedon, S. D., Abeywardana, M. Y., Sheng, X., Nam, E., Lee, K., Chen, M., Waterbury, A. L., Zhao, Y., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108446 · Cited by 13
Synthesis and Assay of SIRT1-Activating Compounds
Dai, H., Ellis, J. L., Sinclair, D. A., & Hubbard, B. P. (2016) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2016.01.012 · Cited by 12
Research advances on epigenetics and cancer metabolism
Han, H., Feng, F., & Li, H. (2021) · Journal of Zhejiang University (Medical Sciences) · doi:10.3724/zdxbyxb-2021-0053 · Cited by 12
“催化去除琥珀酰化、戊二酰化和丙二酰化,但其酶 活性都很低[81-84]。相较于 Sirtuins家族,对于HDAC”
Zessin, M., Meleshin, M., Simic, Z., Kalbas, D., Arbach, M., Gebhardt, P., Melesina, J., Liebscher, S., Bordusa, F., Sippl, W., et al. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.105425 · Cited by 12
Novel post-translational modifications in the kidneys for human health and diseases
Xiang, T., Zhao, S., Wu, Y., Li, L., Fu, P., & Ma, L. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121188 · Cited by 13
Proteomics of Long‐Lived Mammals
Tombline, G., Gigas, J., Macoretta, N., Zacher, M., Emmrich, S., Zhao, Y., Seluanov, A., & Gorbunova, V. A. (2019) · PROTEOMICS · doi:10.1002/pmic.201800416 · Cited by 12
Liu, Z., Yang, T., Li, X., Peng, T., Hang, H. C., & Li, X. (2014) · Angewandte Chemie · doi:10.1002/ange.201408763 · Cited by 12
Sirtuins, Healthspan, and Longevity in Mammals
Giblin, W., & Lombard, D. B. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-411596-5.00003-4 · Cited by 12
Zeng, Y.-Y., Feng, L., Jiang, W., Liu, Y., Wu, P., Jiang, J., Kuang, S., Tang, L. Y., Tang, W., Zhang, Y., et al. (2017) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2017.01.003 · Cited by 12
Sirtuin activation as a therapeutic approach against inborn errors of metabolism
Bleeker, J. C., & Houtkooper, R. H. (2016) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-016-9939-8 · Cited by 11
“This member of the sirtuin family, which will be discussed in a later section, preferentially removes long-chain acyl groups from lysine residues, including hexanoyl, octanoyl, decanoyl, dodecanoyl, palmitoyl and oleoyl chains (Feldman et al 2013).”
Promising drug discovery strategies for sirtuin modulators: what lessons have we learnt?
Garg, G., Singh, A. K., Singh, S., & Rizvi, S. I. (2021) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2021.1915980 · Cited by 11
“Out of these, SirReal2 showed the most promising inhibitory properties [160].”
BackgroundSIRT2 tyrosine nitration by peroxynitrite in response to renal ischemia/reperfusion injury
Wang, Y., Wu, C. J., Du, Y., Liu, Y. Q., Cai, J. R., Wu, X. Q., & Hu, S. Q. (2021) · Free Radical Research · doi:10.1080/10715762.2021.2024529 · Cited by 11
“Previous structural analysis of the sirtuin family members revealed a conserved catalytic core composed of two subdomains, a Rossmann fold domain at one end and a smaller, more variable zincbinding domain at the opposite end that plays important roles in substrate binding and modification regulation [50,51].”
BackgroundRoessler, C., Nowak, T., Pannek, M., Gertz, M., Nguyen, G. T. T., Scharfe, M., Born, I., Sippl, W., Steegborn, C., & Schutkowski, M. (2014) · Angewandte Chemie · doi:10.1002/ange.201402679 · Cited by 11
Protein crotonylation: An emerging regulator in DNA damage response
Ji, P., Zhang, G., Guo, Y., Song, H., Yuan, X., Hu, X., Guo, Z., Xia, P., Shen, R., & Wang, D. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122059 · Cited by 11
Biophysical characterization of hit compounds for mechanism-based enzyme activation
Guan, X., Upadhyay, A., Munshi, S., & Chakrabarti, R. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194175 · Cited by 11
Sasazaki, S., Kawaguchi, F., Nakajima, A., Yamamoto, R., Akiyama, T., Kohama, N., Yoshida, E., Kobayashi, E., Honda, T., Oyama, K., et al. (2020) · Animal Science Journal · doi:10.1111/asj.13335 · Cited by 11
Dietary fatty acids as nutritional modulators of sirtuins: a systematic review
Caldas, A. P. S., Rocha, D. M. U. P., Bressan, J., & Hermsdorff, H. H. M. (2020) · Nutrition Reviews · doi:10.1093/nutrit/nuaa007 · Cited by 11
Substrate-Dependent Modulation of SIRT2 by a Fluorescent Probe, 1-Aminoanthracene
Bi, D., Yang, J., Hong, J. Y., Parikh, P., Hinds, N. M., Infanti, J., Lin, H., & Weiser, B. P. (2020) · Biochemistry · doi:10.1021/acs.biochem.0c00564 · Cited by 11
Consequences of circadian dysregulation on metabolism
Nelson, R. J., & Cissé, Y. M. (2016) · ChronoPhysiology and Therapy · doi:10.2147/cpt.s100363 · Cited by 12
“activated by fatty acids, providing additional metabolite integration.(70) Together, these studies suggest that altered”
Dehomocysteinylation is catalysed by the sirtuin‐2‐like bacterial lysine deacetylase CobB
Mei, X., He, X., Huang, L., Qi, D., Nie, J., Li, Y., Si, W., & Zhao, S. (2016) · FEBS Journal · doi:10.1111/febs.13912 · Cited by 12
Rooker, D. R., Klyubka, Y., Gautam, R., Tomat, E., & Buccella, D. (2017) · ChemBioChem · doi:10.1002/cbic.201700582 · Cited by 11
Protein hypoacylation induced by Sirt5 overexpression has minimal metabolic effect in mice
Bentley, N. L., Fiveash, C. E., Osborne, B., Quek, L., Ogura, M., Inagaki, N., Cooney, G. J., Polly, P., Montgomery, M. K., & Turner, N. A. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.07.047 · Cited by 11
Nakajima, Y., Kawaguchi, M., Ieda, N., & Nakagawa, H. (2021) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00010 · Cited by 10
Protein lysine four‐carbon acylations in health and disease
Fang, Y., & Li, X. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.30981 · Cited by 10
“HDAC1, 2, 3, 8 and SIRT1,2,3 have been shown to remove lysine crotonylation (Bao et al., 2014; Feldman et al., 2013; Fellows et al., 2018; Kelly et al., 2018; Madsen & Olsen, 2012; Wei, Liu, et al., 2017; W. Xu et al., 2017).”
BackgroundActivation of SIRT6 Deacetylation by DNA Strand Breaks
Kang, W., Hamza, A., Curry, A. M., Korade, E., Donu, D., & Cen, Y. (2023) · ACS Omega · doi:10.1021/acsomega.3c04859 · Cited by 9
Skeletal phenotypes and molecular mechanisms in aging mice
Guan, Q., 上海体育大学运动健康学院, 上. 2., Zhang, Y., Wang, Z., Liu, X.-H., Zou, J., & Zhang, L.-L. (2024) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2023.397 · Cited by 13
“Long-chain fatty acids have also been shown to effectively enhance SIRT6 enzyme activity (Feldman et al., 2013).”
BackgroundApplication of crotonylation modification in pan-vascular diseases
Yan, W., Zhang, Y., Dai, Y., & Ge, J. (2024) · Journal of drug targeting · doi:10.1080/1061186x.2024.2372316 · Cited by 10
“…only SiRt1, SiRt2, SiRt3 and SiRt6 with the activity of HDAc. the earliest studies identified H3K9 as the acetylation site for SiRt1 and SiRt2 [17]. wei et al. found that ectopic expression of SiRt1 led to a significant decrease in H3K9cr and H4K8cr, as well as a moderate decrease in H3K4cr…”
Sharma, D. K., Panchaksaram, M., & Muniyan, R. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116743 · Cited by 10
Wei, L., Wang, D. S., Sun, J., Wang, X., Shen, Y., & Di, H. (2022) · Food Analytical Methods · doi:10.1007/s12161-022-02301-7 · Cited by 10
“These compounds are considered to be beneficial to human health because of having many effects, including anti-inflammation, decreased tumorigenesis, impairment of insulin-mediated glucose uptake and glycogen synthesis in the muscle, regulation of blood pressure, blood clotting, and functioning of the brain and nervou…”
BackgroundStructural Basis of Sirtuin 6 Activation by Synthetic Small Molecules
You, W., Rotili, D., Li, T., Kambach, C., Meleshin, M., Schutkowski, M., Chua, K. F., Mai, A., & Steegborn, C. (2016) · Angewandte Chemie · doi:10.1002/ange.201610082 · Cited by 10
Yu, J., Haldar, M., Mallik, S., & Srivastava, D. K. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152467 · Cited by 9
“recently demonstrated that SIRT1-SIRT6 all possess the potential to catalyze the deacylation reactions of fatty acyl-lysine conjugates in peptides/proteins [10, 11].”
BackgroundKollenstart, L., van der Horst, S. C., Vreeken, K., Janssen, G. M. C., Martino, F., Vlaming, H., van Veelen, P. A., van Leeuwen, F., & van Attikum, H. (2021) · Scientific Reports · doi:10.1038/s41598-021-91359-0 · Cited by 12
SIRT7 Is a Lysine Deacylase with a Preference for Depropionylation and Demyristoylation
Kibria, M. G., Yoshizawa, T., Zhang, T., Ono, K., Mizumoto, T., Sato, Y., Sawa, T., & Yamagata, K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26073153 · Cited by 10
“SIRT6 preferentially removes long-chain fatty acyl groups, such as myristoyl and palmitoyl groups, from lysine residues and promotes tumor necrosis factor-α secretion [13,14].”
Li, X., Kabza, A. M., Ives, A. N., Thiel, J., Waters, K. M., Qian, W., Sims, A. M., & Zhang, T. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1587106 · Cited by 11
Site-Specific Lysine Acetylation Stoichiometry Across Subcellular Compartments
Lindahl, A. J., Lawton, A. J., Baeza, J., Dowell, J. A., & Denu, J. M. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9434-2_6 · Cited by 9
Self-citationYuan, T., Keijer, J., Guo, A. H., Lombard, D. B., & de Boer, V. C. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-72833-7 · Cited by 9
Tang, L., Remiszewski, S., Snedeker, A., Chiang, L. W., & Shenk, T. E. (2024) · Antiviral Research · doi:10.1016/j.antiviral.2024.105888 · Cited by 9
Wang, Z. A., Hsu, W. W., & Liu, W. R. (2019) · Springer eBooks · doi:10.1007/978-3-319-55530-0_1 · Cited by 9
QSAR studies on the human sirtuin 2 inhibition by non-covalent 7,5,2-anilinobenzamide derivatives
Ferreira, G. M., Magalhães, J. G., Maltarollo, V. G., Kronenberger, T., Ganesan, A., Emery, F. D. S., & Trossini, G. H. G. (2019) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2019.1574603 · Cited by 9
Unexpected small molecules as novel SIRT2 suicide inhibitors
Chen, X., Zou, Y., Wang, J., Cao, Z., Liu, J., Li, Y., Zhao, Y., & He, B. (2020) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2020.115353 · Cited by 9
β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice
Huynh, F. K., Peterson, B. S., Anderson, K. A., Lin, Z., Coakley, A. J., Llaguno, F. M. S., Nguyen, T.-T. N., Campbell, J. E., Stephens, S. B., Newgard, C. B., et al. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00170.2020 · Cited by 9
Divya, K. P., Kanwar, N., Anuranjana, P. V., Kumar, G., Beegum, F., George, K. T., Kumar, N., Nandakumar, K., & Kanwal, A. (2024) · Cardiovascular Toxicology · doi:10.1007/s12012-024-09858-1 · Cited by 11
“It was found that the free fatty acids stimulated SIRT6 deacetylase activity at varied fold levels [148].”
A ternary complex model of Sirtuin4-NAD+-Glutamate dehydrogenase
Kato, Y. S., Kihara, H., Fukui, K., & Kojima, M. (2018) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2018.03.006 · Cited by 9
“Sirt4 was previously reported to lack deacetylase activity [5]; however, recent studies have indicated the possibility of deacetylase and delipoylase activities [6-9].”
BackgroundSociali, G., Liessi, N., Grozio, A., Caffa, I., Parenti, M. D., Ravera, S., Tasso, B., Benzi, A., Nencioni, A., Río, A. D., et al. (2019) · Molecular Diversity · doi:10.1007/s11030-019-09971-2 · Cited by 9
Zhu, G.-R., Zheng, X., Wang, Z., & Xu, X. (2022) · Biomolecules · doi:10.3390/biom12111655 · Cited by 8
Reading and erasing of histone crotonyllysine mimics by the AF9 YEATS domain and SIRT2 deacylase
Bilgin, N., Türkmen, V. A., Hammami, N., Christensen, N. R., Hintzen, J. C. J., & Mecinović, J. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117500 · Cited by 8
Protein crotonylation: Basic research and clinical diseases
Li, D., Lin, L., Xu, F., Feng, T., Tao, Y., Miao, H., & Yang, F. (2024) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2024.101694 · Cited by 8
“Moreover, SIRT1, SIRT2, and SIRT3 were all confirmed that they have the ability of histone decrotonylases in vitro [36,37].”
BackgroundEmerging posttranslational modifications and their roles in DNA damage response
Wu, Z., Liu, Y., Zhang, M., & Wang, D. (2023) · Genome Instability & Disease · doi:10.1007/s42764-023-00115-3 · Cited by 8
“Studies have found that SIRT1 and SIRT2 can also act as decro-tonylases, effectively removing crotonylation on the H3K9 peptide modified by histone crotonylation (Feldman et al., 2013).”
Development of Second Generation Activity-Based Chemical Probes for Sirtuins
Curry, A. M., Barton, E. E., Kang, W., Mongeluzi, D. V., & Cen, Y. (2020) · Molecules · doi:10.3390/molecules26010011 · Cited by 8
“A previous study suggested that SIRT1, SIRT2, and SIRT6 have strong deacylase activity against long-chain fatty acyl groups such as myristoyl [39].”
InfluentialRole of sirtuins in cardiovascular diseases
Ravi, V., Mishra, S., & Sundaresan, N. R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814118-2.00021-5 · Cited by 7
Distribution and diversity of classical deacylases in bacteria
Graf, L. G., Moreno–Yruela, C., Qin, C., Schulze, S., Palm, G. J., Schmöker, O., Wang, N., Hocking, D. M., Jebeli, L., Girbardt, B., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53903-0 · Cited by 7
Sun, W., Chen, H., Hou, H., Xue, H., Yang, Q., & He, G. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103608 · Cited by 7
“In general, Kcro could be catalyzed by universal lysine acetyltransferases, such as the CREB-binding protein (CBP)/p300 [22,25], and removed by specific histone deacetylases (HDACs), including HDAC1/2/3 and sirtuin1/2/3 [17,26,27].”
KDAC8 with High Basal Velocity Is Not Activated by N-Acetylthioureas
Toro, T. B., Pingali, S. R. K., Nguyen, T. P., Garrett, D. S., Dodson, K., Nichols, K. A., Haynes, R. A., Payton‐Stewart, F., & Watt, T. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0146900 · Cited by 7
Strukturbasierte Entwicklung einer Affinitätssonde für Sirtuin 2
Schiedel, M., Rumpf, T., Karaman, B., Lehotzky, A., Gerhardt, S., Ovádi, J., Sippl, W., Einsle, O., & Jung, M. (2015) · Angewandte Chemie · doi:10.1002/ange.201509843 · Cited by 7
SIRT6 mediates multidimensional modulation to maintain organism homeostasis
Yang, Y., Zhu, M. L., Liang, J., Wang, H., Sun, D., Li, H., & Chen, L. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30791 · Cited by 7
“…has been depleted from the L1 locus (Van Meter, M., Kashyap et al., 2014) 2.2.3 | Lysine long‐chain fatty acid deacylation Studies have found that free fatty acids can bind to and activate the deacetylation activity of SIRT6, causing by the unique hydrophobic pocket of SIRT6 (Feldman et al., 2013).”
BackgroundInfluentialKalbas, D., Meleshin, M., Liebscher, S., Zessin, M., Melesina, J., Schiene‐Fischer, C., Bülbül, E. F., Bordusa, F., Sippl, W., & Schutkowski, M. (2022) · Biochemistry · doi:10.1021/acs.biochem.2c00211 · Cited by 7
Sirtuin 6 Is a Critical Epigenetic Regulator of Cancer
Raghu, S., Prabhashankar, A. B., Shivanaiah, B., Tripathi, E., & Sundaresan, N. R. (2022) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-07634-3_10 · Cited by 7
Structure-Based Design and Computational Studies of Sirtuin Inhibitors
Karaman, B., Jung, M., & Sippl, W. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802808-7.00011-3 · Cited by 7
A one-step specific assay for continuous detection of sirtuin 2 activity
Dai, Q., Zheng, Z., Xia, F., Liu, P., & Li, M. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.05.007 · Cited by 7
Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology
Sanderson, J. M. (2020) · BioEssays · doi:10.1002/bies.201900147 · Cited by 7
Sirtuin 6 (SIRT6) Activity Assays
Rahnasto‐Rilla, M., Lahtela-Kakkonen, M. K., & Moaddel, R. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3667-0_17 · Cited by 7
“These assays have the added advantage in that they have been demonstrated to be robust in determining both the inhibition and activation activity of the tested compounds for SIRT6 and are discussed in greater detail below [6, 13].”
BackgroundMethodZhu, A., Ye, T., Tan, M., & Xu, J. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.147964 · Cited by 7
Jos, S., Aouti, S., Unni, S., Haridass, V., Gogoi, H., Deshmukh, P. H., Padmanabhan, B., & Padavattan, S. (2021) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2021.1938229 · Cited by 6
“The SIRT6 has diverse enzymatic activities among sirtuin family members: deacetylation, defatty-acylation and monoADP-ribosylation (Feldman et al., 2013; Jiang et al., 2013; Mao et al., 2011; Zhang et al., 2016).”
BackgroundInhibition of Sirtuin Deacylase Activity by Peroxynitrite
Bohl, K. S., Wynia‐Smith, S. L., Jones, R. A., & Smith, B. C. (2024) · Biochemistry · doi:10.1021/acs.biochem.4c00257 · Cited by 6
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 · doi:10.1002/ange.202200303 · Cited by 6
Wang, J., Zang, W., Liu, J., & Zheng, W. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.11.082 · Cited by 6
Bonomi, R. E., Laws, M. T., Popov, V., Kamal, S., Potukutchi, S., Shavrin, A., Lu, X., Turkman, N., Liu, R.-S., Mangner, T. J., et al. (2018) · Molecular Imaging and Biology · doi:10.1007/s11307-017-1149-8 · Cited by 6
“These observations agree with previous reports, demonstrating a similar trend in SIRT2 catalytic efficiency for the H3K9 peptide backbone derivatized with hexanoyl, octanoyl, decanoyl, dodecanoyl, and myristoyl groups, but significantly less efficiently the palmitoyl and lipoyl-derivatized H3K9 peptide [23, 24].”
The Enzymatic Activities of Sirtuins
Lin, H. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813499-3.00004-6 · Cited by 6
Hong, J. Y., Cassel, J. A., Yang, J., Lin, H., & Weiser, B. P. (2021) · ChemMedChem · doi:10.1002/cmdc.202100343 · Cited by 6
Timuçin, A. C., & Başağa, H. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161494 · Cited by 6
“IV) Finally, it is important to note that SIRT6 may directly induce several post translational modifications including deacetylation and/or depalmitoylation on NFAT5 for upregulation of AR [12].”
BackgroundInfluentialIbrahim, M. A. A., Abdeljawaad, K. A. A., Abdelrahman, A. H. M., Arzumanyan, G., Mekhemer, G. A. H., Abdelbacki, A. M. M., Sidhom, P. A., Sayed, S. R. M., & Hegazy, M. F. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.151701 · Cited by 7
Protocol to purify the histone deacetylase SIRT6 and assess its activity in vitro
Tian, Y., Feng, T., Hou, T., & Zhu, W. (2023) · STAR Protocols · doi:10.1016/j.xpro.2023.102206 · Cited by 5
Development of Lysine Crotonyl‐Mimic Probe to Covalently Identify H3K27Cr Interacting Proteins
Guo, X., Wang, Y., An, Y., Liu, Z., Liu, J., Chen, J., Zhan, M., Liang, M., Hou, Z., Wan, C., et al. (2023) · Chemistry - A European Journal · doi:10.1002/chem.202301624 · Cited by 5
Cracking Lysine Crotonylation (Kcr): Enlightening a Promising Post‐Translational Modification
Westerveld, M., Besermenji, K., Aidukas, D., Ostrovitsa, N., & Petracca, R. (2024) · ChemBioChem · doi:10.1002/cbic.202400639 · Cited by 6
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
