The DOI matches its Crossref record; 86 of the 87 references it cites were found in a registry or an index.
SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion
Open accessAbstract
Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.
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
“One study has shown that SIRT4 can regulate the levels of both lipoyl- and biotinyl-lysine modifications in pyruvate dehydrogenase and likely other proteins ((Mathias et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Anderson 2017
In the citing paper
“For example, SIRT4 has been shown to cleave e -N -lipoyllysine (Klip) (Mathias et al., 2014) and e -N -(3-methylglutaconyl)lysine (Kmgc) (Anderson et al., 2017), SIRT5 regulates e -N -malonyllysine (Kmal) (Du et al., 2011; Peng et al., 2011; Hirschey and Zhao, 2015; Nishida et al., 2015), e -N -succinyllysine (Ksuc) (Du et al., 2011; Park et al., 2013; Rardin et al., 2013; Hirschey and Zhao, 2015)”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Anderson et al., 2017
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
Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega
Sievers, F., Wilm, A., Dineen, D., Gibson, T., Karplus, K., Li, W.-Z., Lopez, R., McWilliam, H., Remmert, M., Söding, J., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.75 · Cited by 15,576 · cited 1×
“This bacterial enzyme is homologous to murine MCCC, with sequence identities of 47% and 66% for the a and b subunits, respectively (Sievers et al., 2011).”
BackgroundSelf-citationFastTree 2 – Approximately Maximum-Likelihood Trees for Large Alignments
Price, M. N., Dehal, P. S., & Arkin, A. P. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009490 · Cited by 14,894 · cited 2×
“We built a phylogenetic tree from the sirtuin domain portions of all of these sequences with length greater than 40 residues using the WAG-CAT model in FastTreeMP (Price et al., 2010), version 2.1.8.”
MethodInfluentialCHARMM: The biomolecular simulation program
Brooks, B. R., Brooks, C. L., MacKerell, A. D., Nilsson, L., Petrella, R. J., Roux, B., Won, Y., Archontis, G., Bartels, C., Boresch, S., et al. (2009) · Journal of Computational Chemistry · doi:10.1002/jcc.21287 · Cited by 9,115 · cited 3×
“Each mouse subunit was superimposed over the corresponding subunits in the crystal structure template by sequence alignment and the resulting complex typed with the CHARMM forcefield (Brooks et al., 2009) and energy minimized with the smart minimizer protocol using the Generalized-Born with simple switching implicit s…”
MethodPfam: the protein families database
Finn, R. D., Bateman, A., Clements, J., Coggill, P., Eberhardt, R. Y., Eddy, S. R., Heger, A., Hetherington, K., Holm, L., Mistry, J., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1223 · Cited by 6,148
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510 · cited 2×
“Originally thought to be strictly lysine deacetylases (Imai et al., 2000; Verdin et al., 2004) or ADP-ribosyltransferases (Tanny et al., 1999), more recent studies have shown that the sirtuins remove several post-translational modifications (PTMs) from lysine residues (Anderson et al., 2014).”
Background2016 update of the PRIDE database and its related tools
Vizcaíno, J. A., Csordás, A., del‐Toro, N., Dianes, J. A., Griss, J., Lavidas, I., Mayer, G., Pérez‐Riverol, Y., Reisinger, F., Ternent, T., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1145 · Cited by 3,466 · cited 2×
“The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (Vizcaı́no et al., 2016) partner repository with the dataset identifier PRIDE: PXD005896.”
MethodNewgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., Haqq, A. M., Shah, S. H., Arlotto, M., Slentz, C. A., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.002 · Cited by 3,165 · cited 2×
“Previous studies have shown that altered BCAA metabolism is associated with the progression of diabetes and cardiovascular disease (Newgard et al., 2009; Shah et al., 2010).”
BackgroundSelf-citationHMDB 3.0—The Human Metabolome Database in 2013
Wishart, D. S., Jewison, T., Guo, A. C., Wilson, M., Knox, C., Liu, Y., Djoumbou-Feunang, Y., Mandal, R., Aziat, F., Dong, E., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1065 · Cited by 2,845 · cited 4×
“Interestingly, the structurally similar 3-methylglutaconyl-CoA (MGc-CoA; Figure 3A) is an intermediary metabolite in leucine catabolism (Wishart et al., 2013) and MG-CoA is thought to originate from the chemical or enzymatic reduction of MGc-CoA (Roe et al.”
BackgroundInfluentialSirtuins as regulators of metabolism and healthspan
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008 · cited 1×
“Conversely, ablation or inhibition of sirtuins accelerates the onset of several aging phenotypes (Houtkooper et al., 2012).”
BackgroundProtein Structure Modeling with MODELLER
Eswar, N., Eramian, D., Webb, B., Shen, M., & Šali, A. (2008) · Methods in molecular biology · doi:10.1007/978-1-60327-058-8_8 · Cited by 1,781
Flagged first, then by citations
1 of the 87 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 201–300 of 330
Loss of mitochondrial SIRT4 shortens lifespan and leads to a decline in physical activity
Parik, S., Tewary, S., Ayyub, C., & Kolthur‐Seetharam, U. (2018) · Journal of Biosciences · doi:10.1007/s12038-018-9754-5 · Cited by 13
Ordway, B., Swietach, P., Gillies, R. J., & Damaghi, M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00373 · Cited by 13
“SIRT4 is a lysine deacylase (Figure 2) (42), that has the ability to inhibit glutamine metabolism by inhibiting glutamate dehydrogenase (GDH).”
BackgroundMetabolic pathways at the crossroads of diabetes and inborn errors
Goetzman, E. S., Gong, Z., Schiff, M., Wang, Y., & Muzumdar, R. H. (2017) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-017-0091-x · Cited by 16
“Sirt4 knockout mice showed elevated leucine-stimulated insulin secretion, which as the mice age develops into glucose intolerance (Anderson et al 2017; Huynh et al 2017).”
BackgroundXu, Q., Chen, Z., Wang, R., Ma, X., Duan, Y., Hai, D., Jing, C., Cheng, Z., Zheng, L., Huang, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61474-x · Cited by 12
“Classically annotated HDACs were previously identi fi ed based on their ability to carry out acetylation and other acetylation-independent acylation reactions 30,43,57,58 .”
Lu, X., Wu, K., Jiang, S., Li, Y., Wang, Y., Li, H., Li, G., Liu, Q., Zhou, Y., Chen, W., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1153503 · Cited by 12
“The structure was minimized with the MMFF94 force field (Anderson et al., 2017).”
MethodMitochondrial Tumor Suppressors—The Energetic Enemies of Tumor Progression
Jakoubě, P., Cutano, V., González-Morena, J. M., & Keckesova, Z. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0518 · Cited by 13
“It has been found that SIRT4 also has a lysine deacylase enzymatic activity; it removes acyl moieties from lysine residues (methylglutaryl-, hydroxymethylglutaryl-, and 3-methylglutaconyl-lysine), thus affecting leucine metabolism and insulin secretion (129).”
BackgroundSIRT4 Is Highly Expressed in Retinal Müller Glial Cells
Wei, W., Hu, P., Qin, M., Chen, G., Wang, F., Yao, S., Jin, M., Xie, Z., & Zhang, X. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.840443 · Cited by 12
“Recently, there have been new insights into the activity of SIRT4 that SIRT4 is a lysine deacylase (Anderson et al., 2017).”
BackgroundWang, C., Piao, C., Liu, J., Zhang, Z., Zhu, Y., & Kong, C. (2020) · Cancer Biomarkers · doi:10.3233/cbm-191253 · Cited by 12
“In addition, SIRT4 also participated in regulating leucine metabolism and ATP homeostasis [16,17].”
Dutra, H. L. C., Deehan, M., & Frydman, H. M. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008996 · Cited by 12
“In parallel to GDH-dependent ATP production, SIRT4 also acts through the inner mitochondrial transmembrane protein adenine nucleotide translocator 2 (ANT2), an ATP/ADP translocator [56], and methylcrotonyl-CoA carboxylase enzyme (MCCC), involved in leucine catabolism [57] in order to mediate cellular ATP homeostasis.”
BackgroundSirtuins, 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
Cao, Y., Wang, Y., Zhao, N., Yuan, Z., Zhang, L. H., & Jin, P. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156356 · Cited by 11
Liang, M., Deng, S., Zhang, Y., Guo, J., Lie, Z., Yang, Y., Dai, G., & Liu, X. (2025) · Plant Communications · doi:10.1016/j.xplc.2025.101424 · Cited by 11
Role of non‐enzymatic chemical reactions in 3‐methylglutaconic aciduria
Jones, D. E., Romenskaia, I., Kosma, D. K., & Ryan, R. O. (2021) · FEBS Journal · doi:10.1111/febs.16316 · Cited by 11
Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism
Jones, D. E., Jennings, E. A., & Ryan, R. O. (2022) · Metabolites · doi:10.3390/metabo12050377 · Cited by 11
“Once formed, 3MGCylated proteins can be deacylated through the action of sirtuin 4 (SIRT4) [24], producing cis‐3MGC acid as a product.”
BackgroundInfluentialMuroski, J. M., Fu, J. Y., Nguyen, H. H., Wofford, N. Q., Mouttaki, H., James, K. L., McInerney, M. J., Gunsalus, R. P., Loo, J. A., & Loo, R. R. O. (2022) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2022.100215 · Cited by 11
“Interestingly, the sirtuin assayed in this system appears to have a bias for longer chain acylations, particularly glutarylation, a trait that is shared with Sirt4 and Sirt5 in mammalian systems (66, 85, 86).”
BackgroundProtein 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
Ruocco, C., Malavazos, A. E., Ragni, M., Carruba, M. O., Valerio, A., Iacobellis, G., & Nisoli, E. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106892 · Cited by 10
“Given recent evidence that branched acyl lysine modifications also alter mitochondrial enzyme function [89], it is possible that diversion of branched CoA intermediates to long chain FAs via CrAT is beneficial for maintaining healthy mitochondrial function.”
Li, Q., Fu, C., Hu, B., Yang, B., Yu, H., He, H., Xu, Q., Chen, X., Dai, X., Fang, R., et al. (2024) · The Plant Journal · doi:10.1111/tpj.16815 · Cited by 9
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
Yuan, 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
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
Self-citationIsomerization of trans‐3‐methylglutaconic acid
Jones, D. E., Ricker, J. D., Geary, L. M., Kosma, D. K., & Ryan, R. O. (2020) · JIMD Reports · doi:10.1002/jmd2.12185 · Cited by 8
Pharmacometabolomics of sulfonylureas in patients with type 2 diabetes: a cross-sectional study
Naja, K., Anwardeen, N. R., Bashraheel, S. S., & Elrayess, M. A. (2024) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.3389/jpps.2024.13305 · Cited by 8
SIRT5: a potential target for discovering bioactive natural products
Xie, Y., Cai, N., Liu, X., He, L., Ma, Y., Yan, C., Liang, J., Ouyang, S., Luo, A., He, Y., et al. (2025) · Journal of Natural Medicines · doi:10.1007/s11418-024-01871-6 · Cited by 10
The role of protein acetylation in regulating mitochondrial fusion and fission
Uddin, G. M., Abbas, R., & Shutt, T. E. (2021) · Biochemical Society Transactions · doi:10.1042/bst20210798 · Cited by 8
Sirtuins—Novel Regulators of Epigenetic Alterations in Airway Inflammation
Wu, S., & Liu, H. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.862577 · Cited by 8
“In the case of activators, binding sites are usually not easily detected by crystal structure examination, and there is no general and systematic strategy to identify and target these sites (Anderson et al., 2017).”
BackgroundShrimp SIRT4 promotes white spot syndrome virus replication
Tan, Y. K., Castillo-Corea, B. R. D. J., Kumar, R., Lai, P.-H., Lin, S., & Wang, H. (2023) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2023.109328 · Cited by 8
Lensu, S., Pekkala, S., Mäkinen, A., Karstunen, N., Turpeinen, A., Hulmi, J. J., Silvennoinen, M., Ma, H., Kujala, U. M., Karvinen, S. M., et al. (2019) · Metabolism Open · doi:10.1016/j.metop.2019.100019 · Cited by 8
“activity is controlling BCAA catabolism [20]) was enhanced by 2fold in response to running (p< 0.”
BackgroundInfluentialtrans-3-Methylglutaconyl CoA isomerization-dependent protein acylation
Young, R., Jones, D. E., Diacovich, L., Witkowski, A., & Ryan, R. O. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.11.100 · Cited by 8
“In vivo, the NAD+-dependent deacylase, sirtuin-4, has been shown to catalyze removal of acyl groups from 3MGCylated proteins [15,16].”
BackgroundRole 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
Self-citationRole of Branched-Chain Amino Acid Catabolism in the Regulation of Adipocyte Metabolism
Jiang, H., Guo, F., & Xiao, F. (2025) · Endocrinology · doi:10.1210/endocr/bqaf089 · Cited by 9
Association between mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) and PCOS
Huang, L.-Y., Qin, X., Tian, C., Ling, S., Luo, X., Huang, B., Ling, Y., Zhong, S., Li, Z., & Li, Q. (2025) · European journal of medical research · doi:10.1186/s40001-025-02862-3 · Cited by 8
Mitochondrial VHL rewires cell metabolism in hypoxia
Li, G., Pan, W., Wu, L., Cai, Z., Chen, H., Wu, X., Yu, T., Liao, K., Zhang, H., 温星桥, et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.11.013 · Cited by 10
Li, Y., Zhao, Y., Cao, Z., Wang, J., Liu, T., Li, Y., Wang, Y., & He, B. (2021) · RSC Advances · doi:10.1039/d0ra09424b · Cited by 5
Lin, S., Teng, L.-Z., Lin, Y., Miao, L., Ge, X., Hao, J.-Y., Huang, X., & Liu, B. (2019) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2019.01.010 · 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
Protein Lysine Acetylation: Grease or Sand in the Gears of β-Cell Mitochondria?
Domingo, J. S., Dayon, L., & Wiederkehr, A. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.09.011 · Cited by 7
Spray-type modifications: an emerging paradigm in post-translational modifications
Lee, Y., & Rhee, H. (2024) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.01.008 · Cited by 6
Li, J., Wang, Y., Niu, X., Xing, J., Dou, Y., Yao, Y., Liang, Y., Wang, Z., Wang, Q., Haiyan, F., et al. (2024) · British Journal of Dermatology · doi:10.1093/bjd/ljae194 · Cited by 6
Advances of SIRT4 in cancer metabolism and therapy
Yue, X., Shi, Y., & Luo, Q. (2023) · Pediatric Discovery · doi:10.1002/pdi3.17 · Cited by 6
“39 Branched‐chain amino acids are the most consumed metabolites during adipocyte differentiation.”
A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue
Wadsworth, B. J., Leiwe, M., Minogue, E., Cunha, P. P., Engman, V., Brombach, C., Asvestis, C., Sah‐Teli, S. K., Marklund, E., Koivunen, P., et al. (2023) · eLife · doi:10.7554/elife.92707 · Cited by 10
“Sirtuin 4 (SIRT4) is localised to the mitochondria and is previously described to induce increased expression and post-translational activation of the BCAA degradation pathway ( Anderson et al., 2017 ; Zaganjor et al., 2021 ).”
BackgroundLi, W., Tu, J., Zheng, J., Das, A., Qi, Y., Jiang, X., Ding, W., Bai, X., Lai, K., Yang, S., et al. (2025) · JOR Spine · doi:10.1002/jsp2.70042 · Cited by 7
“Previous work identified the link between SIRT4 and BCAA catabolism through MCCC1 in the liver [61].”
Pukhalskaia, A. E., Diatlova, A., Linkova, N. S., & Kvetnoy, I. M. (2022) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-022-01217-3 · Cited by 6
“NADPH is a molecule required to counter oxidative damage, maintaining gluThe idea that SIRTs are involved in regulating the oxidation-reduction balance was confi rmed by their interaction with various molecules – antioxidant response elements (ARE), which mediate signal cascades regulating gene transcription in cells…”
BackgroundInfluentialThe Enzymatic Activities of Sirtuins
Lin, H. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813499-3.00004-6 · Cited by 6
Ray, S. K., & Mukherjee, S. (2021) · Free Radical Research · doi:10.1080/10715762.2021.1877286 · Cited by 6
“Researchers have reported mitochondrial SIRT4 (sirtuin 4), which works as lysine deacylase control Leu catabolism and secretion of insulin and may link BCAA metabolism and insulin emission [66].”
BackgroundZhong, Y., Shen, C., Peng, Y., Li, K., Li, Q., Song, Y., Zhou, B., & Rao, L. (2021) · Biomarkers in Medicine · doi:10.2217/bmm-2021-0363 · Cited by 5
Umezawa, K., Tsumoto, H., Kawakami, K., & Miura, Y. (2022) · The Analyst · doi:10.1039/d2an01370c · Cited by 5
Characterization of trans-3-Methylglutaconyl CoA-Dependent Protein Acylation
Jennings, E. A., Cao, E., Romenskaia, I., & Ryan, R. O. (2023) · Metabolites · doi:10.3390/metabo13070862 · Cited by 5
“Although the NAD+-dependent deacylase, sirtuin 4, is able to remove 3MGC moieties from proteins [15], the efficiency with which this occurs is unknown.”
BackgroundTejedor, J. R., Soriano‐Sexto, A., Beccari, L. L., Castejón‐Fernández, N., Medina, P. C., Sainz‐Ledo, L., Alba‐Linares, J. J., Urdinguio, R. G., Ugarte, M., Fernández, A. F., et al. (2024) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12829 · Cited by 5
Papel pleiotrópico y homeostático de las Sirtuinas en la función biológica humana.
Hernández-Bedolla, M. A., Barajas‐Espinosa, A. R., Ochoa‐Cortés, F., Alonso, D. E. A., Hernández, A. H., Ostoa, Z. B., & Salguero, I. G. D. (2020) · Ciencias Huasteca Boletín Científico de la Escuela Superior de Huejutla · doi:10.29057/esh.v8i16.5721 · Cited by 5
“Del mismo modo, participa en apoptosis, regulación del genoma y envejecimiento.(18,54,89) Se expresa en diferentes tipos celulares como células β pancreáticas, hígado, riñón, corazón, cerebro, vasos sanguíneos, células de músculo vascular liso y músculo estriado; débilmente esta expresado en leucocitos y timo fetal.”
BackgroundSirtuins in metabolic and epigenetic regulation of stem cells
Fang, Y., & Li, X. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822467-0.00004-8 · Cited by 5
Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism
Grice, G. L., Minogue, E., Coates, H. W., Debela, M., Stopforth, R. J., Wit, N., Li, Z., Crowley, J. P., Kaser, A., Kaneider-Kaser, N., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01965-6 · Cited by 5
Structural basis of SIRT2 pre-catalysis NAD + binding dynamics and mechanism
Zhang, N., Pow, K. C., Chen, L., & Hao, Q. (2025) · RSC Chemical Biology · doi:10.1039/d5cb00169b · Cited by 4
Sirtuins in Medicine: Multifaceted Roles in Physiological Processes and Cardiovascular Diseases
Krekora, J., Matuszewska-Brycht, O., Wranicz, J. K., Krejca, M., Kaczmarek, K. A., Merks, P., & Dróżdż, J. (2026) · Biomolecules · doi:10.3390/biom16060793 · Cited by 4
Park, J. W., Tyl, M. D., & Cristea, I. M. (2023) · Biomolecules · doi:10.3390/biom13050869 · Cited by 4
“By promoting the catabolism of leucine [238], SIRT4 may additionally impact mTOR-mediated cell growth by removal of one of its key agonists [246].”
BackgroundSun, T., Xu, C., Song, Q., Yang, X., An, G., Sun, G., & Zhang, Z. (2025) · International Journal of Biological Sciences · doi:10.7150/ijbs.99004 · Cited by 4
“It seems unlikely that SIRT4 affects the acetylation level of MCCC1 as demonstrated here in Figure 3G, which is contradictory to the previous report [7].”
InfluentialLv, J., Zhang, Y. X., Wu, Q., Jiang, P., & Lin, Y. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113906 · Cited by 4
Profiling sirtuin activity using Copper-free click chemistry
Curry, A. M., Cohen, I., Zheng, S. G., Wohlfahrt, J., White, D. S., Donu, D., & Cen, Y. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.105413 · Cited by 4
Wang, P., Chen, D., An, J.-X., Lin, S., Liu, T., Li, Y., Chen, L., & He, B. (2022) · Organic & Biomolecular Chemistry · doi:10.1039/d1ob02347k · Cited by 4
Vaca, H. R., Celentano, A. M., Toscanini, M. A., Hauser, A., Macchiaroli, N., Cuestas, M. L., Nusblat, A. D., Sippl, W., Elissondo, M. C., Jung, M., et al. (2022) · International Journal for Parasitology · doi:10.1016/j.ijpara.2021.12.002 · Cited by 4
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 · doi:10.1002/ange.202115805 · Cited by 5
Self-citationYang, W., van de Ven, R. A. H., & Haigis, M. C. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813499-3.00008-3 · Cited by 4
Sirtuins, melatonin, and the relevance of circadian oscillators
Hardeland, R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814118-2.00011-2 · Cited by 4
Roles for Sirtuins in Cardiovascular Biology
Stein, A., Giblin, W., Guo, A. H., & Lombard, D. B. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813499-3.00012-5 · Cited by 4
The Potential of Epigenetic Compounds in Treating Diabetes
Gray, S. G. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812215-0.00017-0 · Cited by 3
Cycling around Lysine Modifications
Kumar, S., & Lombard, D. B. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.05.006 · Cited by 3
“, show that SIRT4 catalyzes removal of these newly described modifications from lysine residues of target proteins [8].”
BackgroundSirtuins and cellular metabolism in cancers
Dong, Z., & Cui, H. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822467-0.00008-5 · Cited by 3
Metabolic choreography of gene expression: nutrient transactions with the epigenome
Maniyadath, B., Sandra, U. S., & Kolthur‐Seetharam, U. (2020) · Journal of Biosciences · doi:10.1007/s12038-019-9987-y · Cited by 4
Sirtuins, healthspan, and longevity in mammals
Kumar, S., Giblin, W., & Lombard, D. B. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-815962-0.00005-6 · Cited by 2
Hampel, N., Georgy, J., Mehrabipour, M., Lang, A., Lehmkuhl, I., Scheller, J., Ahmadian, M. R., Floss, D. M., & Piekorz, R. P. (2023) · FEBS Open Bio · doi:10.1002/2211-5463.13715 · Cited by 3
“…has been characterized in mitochondria as tumor suppressor and inhibitor of the metabolic gate-keeper enzymes pyruvate dehydrogenase (PDH; [25]) and glutamate dehydrogenase (GDH; [26,27]) as well as based on its deacetylase activity as a regulator of leucine metabolism and insulin secretion [28].”
BackgroundLithocholic acid targets TULP3 to activate sirtuins and AMPK to retard ageingPreprint
Qu, Q., Chen, Y., Wang, Y., Long, S., Wang, W., Yang, H.-Y., Wu, J., Li, M., Tian, X., Wei, X., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.07.570558 · Cited by 3
Nicotinamide Coenzymes and Metabolic Diseases
Lu, T., Qin, Z., & Wu, J. (2025) · Springer eBooks · doi:10.1007/978-981-97-9877-3_27 · Cited by 2
Metabolic origin and significance of 3-methylglutaryl CoA
Jennings, E. A., Abi-Rached, Z. H., & Ryan, R. O. (2025) · Clinica Chimica Acta · doi:10.1016/j.cca.2025.120320 · Cited by 2
Mitochondrial sirtuins sir-2.2 and sir-2.3 regulate lifespan in C. elegans
Chang, S. M., Franklin, L. P., Sattar, S., Moro, C. A., DeGennaro, M. V., LaGanke, N. G., & Hanna‐Rose, W. (2025) · Genetics · doi:10.1093/genetics/iyaf185 · Cited by 2
SIRT Family: Biological Functions and Therapeutic Targets
Wang, J., Jiang, F., ZHANG, F.-Y., Huang, D., Li, X. G., Gao, S., You, H., Wu, Q., Chen, H., & Gong, T. Q. (2026) · MedComm · doi:10.1002/mco2.70866 · Cited by 2
“…carboxylase complex hyperacylation, reduced leucine/BCAA flux, increased glutamate dehydrogenase activity, and increased glucose-and leucine-stimulated insulin secretion, and they develop age-dependent hyperinsulinemia, glucose intolerance, insulin resistance, and hyperglycemia [ 10 ].”
InfluentialThe (patho)physiological roles of the individual deacylase activities of a sirtuin
Zheng, W. (2024) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14460 · Cited by 2
“…each possesses multiple deacylase activities acting on N ε - acyl-lysine substrates with different acyl groups (Figure 1) (Abmayr & Workman, 2019; Anderson et al., 2017; Bheda et al., 2016; Chen et al., 2015; Chio et al., 2023; Colak et al., 2013; Delaney et al., 2021; Dong et al., 2022; Fan et…”
BackgroundFactors Affecting Non-Enzymatic Protein Acylation by trans-3-Methylglutaconyl Coenzyme A
Jennings, E. A., Macdonald, M. M., Romenskaia, I., Yang, H., Mitchell, G. A., & Ryan, R. O. (2024) · Metabolites · doi:10.3390/metabo14080421 · Cited by 2
“Once formed, the anhydride has at least two possible fates, including spontaneous hydrolysis to 3MGC acid or covalent 3MGCylation of protein lysine side In vivo, 3MGCylated proteins are substrates for the NAD + -dependent deacylase, sirtuin 4 [10,11]. chain amino groups [8,9].”
BackgroundDual role of sirtuins in cancer
Torrens‐Mas, M., & Roca, P. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822467-0.00011-5 · Cited by 2
Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation
Grabacka, M., & Plonka, P. M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822467-0.00001-2 · Cited by 3
The bifunctional roles of sirtuins and their therapeutic potential in cancer
Lee, Y. T., Tan, Y. J., Mok, P. Y., Subramaniam, A. V., & Oon, C. E. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822467-0.00009-7 · Cited by 2
Deglutarylation of GCDH by SIRT5 controls lysine metabolism in micePreprint
Bhatt, D. P., Mills, C. A., Anderson, K. A., Henriques, B. J., Lucas, T. G., Francisco, S., Liu, J., Ilkayeva, O., Adams, A. E., Kulkarni, S. R., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.28.176677 · Cited by 2
“To do so, we modified an in vitro leucine oxidation assay (17) for measuring lysine metabolism”
BackgroundMethodSelf-citationAnderson, K. A., deSouza, B., Castellano‐Escuder, P., Lin, Z., Ilkayeva, O., Muehlbauer, M. J., Grimsrud, P. A., & Hirschey, M. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.12.653532 · Cited by 3
“Mice lacking SIRT4 exhibit accelerated development of insulin resistance and defective adipogenesis 11,12 .”
InfluentialSelf-citationSirtuins and mitochondrial dysfunction
He, J., Wang, T.-S., & Wang, Y.-P. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822467-0.00007-3 · Cited by 2
Sirtuins as therapeutic targets in diabetes
Kiełbowski, K., Bratborska, A. W., Bakinowska, E., & Pawlik, A. (2025) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2025.2482563 · Cited by 2
“In a recent study, Anderson et al. [76] demonstrated that SIRT4 modulates leucine metabolism via modifications of lysine residues (methylglutaryl, hydroxymethylglutaryl, and 3-methylglutaconyl).”
The role of SIRT4 in obesity: from molecular mechanisms to clinical implications
Shi, Y., Cao, M., Wang, K., Qi, G., Dong, F., & Zhang, X. (2025) · International Journal of Obesity · doi:10.1038/s41366-025-01945-9 · Cited by 1
“Conversely, SIRT4-KO disrupts leucine metabolism, resulting in intracellular leucine accumulation, GDH activation, and excessive insulin secretion [42, 43].”
Ma, Y., Chen, J., Song, R., & Yu, X. (2026) · Molecular Medicine · doi:10.1186/s10020-026-01503-7 · Cited by 1
“…studies have revealed that SIRT4 possesses potent deacylase activity specifically directed toward complex, negatively charged short-chain acylations, such as hydroxymethylglutarylation (Khmg), methylmalonylation (Kmmal), and glutarylation (Kglu) (Anderson et al. 2017; Zhang et al. 2024).”
Emerging roles of SIRT7 in metabolic homeostasis and related disorders
Yu, S., Rabiu, L., Zhu, W., & Tian, Y. (2026) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2026.168343 · Cited by 1
Nutrient Sensors Regulating Peptides
Çakır, I., & Nillni, E. A. (2018) · Springer eBooks · doi:10.1007/978-3-319-89506-2_6 · Cited by 1
The potential of epigenetic compounds in treating diabetes
Fodor, A., Cozma, A., Sitar-Tăut, A., Vulturar, R., Suharoschi, R., Rusu, A., & Román, G. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-18661-5.00026-9 · Cited by 1
Investigating Physiopathological Roles for Sirtuins in a Mouse Model
Sun, S., Xia, X., Wang, M., & Liu, B. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2788-4_7 · Cited by 1
Li, W., Tu, J., Zheng, J., Das, A., Qi, Y., Jiang, X., Ding, W., Bai, X., Lai, K., Yang, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.26.550629 · Cited by 1
ABHD11 mediated deglutarylation regulates the TCA cycle and T cell metabolismPreprint
Grice, G. L., Minogue, E., Coates, H. W., Debela, M., Kaneider-Kaser, N., Antrobus, R., Johnson, R. S., & Nathan, J. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.11.612392 · Cited by 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
Self-citationMeyer, J. G. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/662841
Yang, Y. J., & Sauve, A. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-409547-2.14664-5
Sirtuins as key players in aging and kidney dysfunction
Perico, L., & Benigni, A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814118-2.00013-6
Faculty Opinions recommendation of The role of sirtuins in antioxidant and redox signaling.
Ji, L. L. (2021) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.731078139.793582081
Rajabi, N., Nielsen, A. L., & Olsen, C. A. (2019) · ChemRxiv · doi:10.26434/chemrxiv.11339774 · Cited by 1
Self-citation
Metadata
- Authors
- Anderson, K. A., Huynh, F. K., Fisher-Wellman, K., Stuart, J. D., Peterson, B. S., Douros, J. D., Wagner, G. R., Thompson, J. W., Madsen, A. S., Green, M. F., Sivley, R. M., Ilkayeva, O. R., Stevens, R. D., Backos, D. S., Capra, J. A., Olsen, C. A., Campbell, J. E., Muoio, D. M., Grimsrud, P. A., & Hirschey, M. D.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- University of Copenhagen (DK)
- Vanderbilt University (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Hirschey, Matthew D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 25
- Issue
- 4
- Pages
- 838-855.e15
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5444661
- OpenAlex
- W2605312736
- Cited by
- 326
- References
- 87
- Citations by year
- 2026: 14 · 2025: 28 · 2024: 31 · 2023: 37 · 2022: 39 · 2021: 47 · 2020: 29 · 2019: 30 · 2018: 49 · 2017: 20
- FWCI
- 21.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Funders
- Vanderbilt University (T32-EY021453)
- Lundbeckfonden (R52-2010-5054)
- National Institute on Aging (P30AG028716-01, R01AG045351)
- Ellison Medical Foundation
- National Institutes of Health
- National Eye Institute
- University of North Carolina at Chapel Hill
- National Institute of Diabetes and Digestive and Kidney Diseases
- Carlsbergfondet (CF15-011, 2011-01-0169, 2013-01-0333)
- National Cancer Institute (CA059365-19)
- Novo Nordisk Fonden (NNF15OC0017334)
- American Heart Association (12SDG8840004, 12IRG9010008)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SIRT4, leucine oxidation, branched-chain amino acids, insulin secretion, insulin resistance, impaired glucose tolerance, glucose homeostasis, aging, mitochondrial sirtuins, post-translational modification
- MeSH terms
- Insulin Secretion, Amidohydrolases, Amino Acid Sequence, Animals, Glucose, Homeostasis, Humans, Insulin, Insulin Resistance, Leucine, Lysine, Mice, Inbred C57BL, Models, Molecular, Phylogeny, Mice, Knockout, Carbon-Carbon Ligases, Mitochondrial Proteins, Sirtuins, HEK293 Cells, Metabolic Flux Analysis
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
