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
Functions and mechanisms of non-histone protein acetylation
Narita, T., Weinert, B. T., & Choudhary, C. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0081-3 · Cited by 1,232
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W. Q., Huang, C., Huber, P., Zhou, X., Li, C. L., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,147
“The lysine deacylase activity of SIRT4 is involved in the control of leucine metabolism and insulin secretion through regulating the acylation status of enzymes in these pathways.(225) SIRT4 also acts as a cellular lipoamidase with a preferred catalytic efficiency for lipoyl- and biotinyl-lysine modifications to its d…”
BackgroundModulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 1,007
The Role of Sirtuins in Antioxidant and Redox Signaling
Singh, C. K., Chhabra, G., Ndiaye, M. A., Garcia‐Peterson, L. M., Mack, N. J., & Ahmad, N. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7290 · Cited by 820
“Interestingly, NADPH is the final reductant for PRDX, and SIRT2 has been shown to deacetylate and inhibit the peroxidase activity of PRDX-1, thereby sensitizing breast cancer cells to oxidative stress-inducing agents (42).”
BackgroundInfluentialNeinast, M. D., Murashige, D., & Arany, Z. P. (2018) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114455 · Cited by 757
“Chem 273(37):23629–32 [PubMed: 9726963]”
BackgroundLipoic acid metabolism and mitochondrial redox regulation
Solmonson, A., & DeBerardinis, R. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000259 · Cited by 505
Sirtuins and NAD + in the Development and Treatment of Metabolic and Cardiovascular Diseases
Kane, A. E., & Sinclair, D. A. (2018) · Circulation Research · doi:10.1161/circresaha.118.312498 · Cited by 497
Sirtuin activators and inhibitors: Promises, achievements, and challenges
Dai, H., Sinclair, D. A., Ellis, J. L., & Steegborn, C. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.03.004 · Cited by 463
The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy
Guo, L., Tian, Y., & Zhu, W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.576946 · Cited by 364
Sirtuins in Renal Health and Disease
Morigi, M., Perico, L., & Benigni, A. (2018) · Journal of the American Society of Nephrology · doi:10.1681/asn.2017111218 · Cited by 359
Carrico, C., Meyer, J. G., He, W., Gibson, B. W., & Verdin, E. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.01.016 · Cited by 331
Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology
Kumar, S., & Lombard, D. B. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1458071 · Cited by 273
“SIRT4 exhibits ADP-ribosyltransferase (Haigis et al. 2006), deacylase (Anderson et al. 2017) as well as substrate-specific deacetylase (Michishita et al. 2005), and lipoamidase activities (Mathias et al. 2014).”
BackgroundMann, G., Mora, S., Madu, G., & Adegoke, O. A. J. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.702826 · Cited by 283
A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation
Wagner, G. R., Bhatt, D. P., O’Connell, T. M., Thompson, J. W., Dubois, L. G., Backos, D. S., Yang, H., Mitchell, G. A., Ilkayeva, O. R., Stevens, R. D., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.006 · Cited by 258
“In other cases, protein damage by lysine acylation could be targeted for removal by sirtuins (Anderson et al., 2017 [this issue of Cell Metabolism]).”
Self-citationMitochondrial sirtuins, metabolism, and aging
Ji, Z., Liu, G., & Qu, J. T. (2021) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2021.11.005 · Cited by 250
p300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis
Huang, H., Tang, S., Ji, M. H., Tang, Z., Shimada, M., Liu, X., Qi, S., Locasale, J. W., Roeder, R. G., Zhao, Y., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.04.011 · Cited by 221
“Significant progress has been made in the identification of deacylation enzymes in the past several years, and the classically annotated HDACs were shown to have activities for not only acetylation but also other acetylation-independent acylations (Anderson et al., 2017; Bheda et al., 2016; Hirschey and Zhao, 2015; Ji…”
BackgroundEnzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues
Wallace, M., Green, C. R., Roberts, L. S., Lee, Y. M., McCarville, J. L., Sánchez-Gurmaches, J., Meurs, N., Gengatharan, J. M., Hover, J. D., Phillips, S. A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0132-2 · Cited by 213
Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio
Anderson, K. A., Madsen, A. S., Olsen, C. A., & Hirschey, M. D. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.09.005 · Cited by 217
“This assay was applied for the discoveries of desuccinylation and deglutarylation by SIRT5 [47, 48], hydrolysis of hydrocarbon-based acyl groups of varying length by the action of SIRT1–3 and 6 [49, 50], and most recently for the discovery of SIRT4 deacylase activity [51].”
MethodSelf-citationNAD+ biosynthesis, aging, and disease
Johnson, S., & Imai, S. (2018) · F1000Research · doi:10.12688/f1000research.12120.1 · Cited by 178
Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins
Palmeira, C. M., Teodoro, J. S., Amorim, J. A., Steegborn, C., Sinclair, D. A., & Rolo, A. P. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.07.017 · Cited by 159
UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer
Hu, Q., Qin, Y., Ji, S., Xu, W., Liu, W., Sun, Q., Zhang, Z., Liu, M., Ni, Q., Yu, X., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.03.024 · Cited by 159
SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy
Lang, A., Anand, R., Altinoluk-Hambüchen, S., Ezzahoini, H., Stefanski, A., Iram, A., Bergmann, L., Urbach, J., Böhler, P., Hänsel, J., et al. (2017) · Aging · doi:10.18632/aging.101307 · Cited by 145
“However, similar to the SIRT4-OPA1 interaction, the molecular mechanism by which SIRT4 impacts on the ERK-DRP1 axis is currently unclear and may require one or more of the known enzymatic activities of SIRT4 (ADP-ribosyltransferase, lipo-AGING amidase, or lysine deacylase; [42-44]).”
Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase
Moreno-Yruela, C., Galleano, I., Madsen, A. S., & Olsen, C. A. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.04.007 · Cited by 149
Self-citationSirtuins and Insulin Resistance
Zhou, S., Tang, X., & Chen, H. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00748 · Cited by 155
“SIRT4 also controls leucine oxidation to regulate insulin secretion (134).”
BackgroundEmerging Roles for SIRT5 in Metabolism and Cancer
Bringman, L. R., Guo, A. H., Lyssiotis, C. A., & Lombard, D. B. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7264 · Cited by 141
The Roles of Mitochondrial SIRT4 in Cellular Metabolism
Min, Z., Gao, J., & Yu, Y. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00783 · Cited by 134
Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3
Zhang, X., Cao, R., Niu, J., Yang, S., Ma, H., Zhao, S., & Li, H. (2019) · Cell Discovery · doi:10.1038/s41421-019-0103-0 · Cited by 128
The roles of sirtuins family in cell metabolism during tumor development
Zhu, S., Dong, Z., Ke, X., Hou, J., Zhao, E., Zhang, K., Wang, F., Yang, L., Xiang, Z., & Cui, H. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.11.003 · Cited by 113
Sirtuin 5 is required for mouse survival in response to cardiac pressure overload
Hershberger, K. A., Abraham, D., Martin, A. S., Mao, L., Liu, J., Gu, H., Locasale, J. W., & Hirschey, M. D. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.809897 · Cited by 105
“SIRT5 possesses demalonylase (3, 4), desuccinylase (4), and deglutarylase (5) activity, whereas SIRT3 is primarily a lysine deacetylase (2), and SIRT4 is a potent lysine deglutarylase, demethylglutarylase,anddehydroxymethylglutarylase (6).”
BackgroundSelf-citationSirtuins, resveratrol and the intertwining cellular pathways connecting them
Ungurianu, A., Zanfirescu, A., & Margina, D. M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101936 · Cited by 114
Human Sirtuin Regulators: The “Success” Stories
Curry, A. M., White, D. S., Donu, D., & Cen, Y. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.752117 · Cited by 107
Pannek, M., Simic, Z., Fuszard, M. A., Meleshin, M., Rotili, D., Mai, A., Schutkowski, M., & Steegborn, C. (2017) · Nature Communications · doi:10.1038/s41467-017-01701-2 · Cited by 103
Dietary Modulation of the Epigenome
Ideraabdullah, F., & Zeisel, S. H. (2018) · Physiological Reviews · doi:10.1152/physrev.00010.2017 · Cited by 99
“The major mechanism by which leucine stimulates insulin secretion involves the allosteric activation of GDH, which as discussed above, is a target of sirtuin 4 (4).”
BackgroundInfluentialSIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
Tyagi, A., Nguyen, C. U., Chong, T., Michel, C. R., Fritz, K. S., Reisdorph, N. A., Knaub, L. A., Reusch, J. E. B., & Pugazhenthi, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-35890-7 · Cited by 98
Wang, C., & Wei, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155266 · Cited by 97
“Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; AceCS2, acetyl-CoA synthetase; ACOX1, acyl-CoA oxidase 1; ANT2, adenine nucleotide translocator 2; CPS1, carbamoyl phosphate synthetase 1; Cu/ZnSOD, Cu/Zn-containing superoxide dismutase; CypD, cyclophilin D; FoxO3A, forkhead box O3A; G6PD, glucose 6-phosphate dehydrogen…”
BackgroundInfluentialKratz, E. M., Sołkiewicz, K., Kubis-Kubiak, A., & Piwowar, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020630 · Cited by 97
“Recently, however, SIRT4 was found to have the ability to deacetylate lysine, allowing it to control leucine metabolism and insulin secretion [57].”
BackgroundInfluentialLiao, L., He, Y., Li, S.-J., Zhang, G.-G., Yu, W., Yang, J., Huang, Z., Zheng, C., He, Q., Li, Y., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-4124 · Cited by 94
Møller, I. M., Igamberdiev, A. U., Bykova, N. V., Finkemeier, I., Rasmusson, A. G., & Schwarzländer, M. (2020) · The Plant Cell · doi:10.1105/tpc.19.00535 · Cited by 89
Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes
Ježek, P., Jabůrek, M., & Plecitá‐Hlavatá, L. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7656 · Cited by 89
“Mitochondrial sirtuin 4 removes three acyl moieties from lysine residues (9).”
BackgroundThe CD38 glycohydrolase and the NAD sink: implications for pathological conditions
Zeidler, J. D., Hogan, K. A., Agorrody, G., Peclat, T., Kashyap, S., Kanamori, K. S., Gomez, L. S., Mazdeh, D. Z., Warner, G. M., Thompson, K. L., et al. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00451.2021 · Cited by 95
Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets
Grootaert, M. O. J., & Bennett, M. R. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00685-x · Cited by 88
Epigenetic regulation in cancer therapy: From mechanisms to clinical advances
Tao, L., Zhou, Y., Luo, Y., Qiu, J., Xiao, Y., Zou, J., Zhang, Y., Liu, X., Yang, X., Gou, K., et al. (2024) · MedComm – Oncology · doi:10.1002/mog2.59 · Cited by 95
Mitochondrial Sirtuins in cardiometabolic diseases
Tang, X., Chen, X., Chen, H., & Liu, D. (2017) · Clinical Science · doi:10.1042/cs20160685 · Cited by 87
SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
Du, Y., Hu, H., Qu, S., Wang, J., Hua, C., Zhang, J., Wei, P., He, X., Hao, J., Liu, P., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.037 · Cited by 87
“an open access article under as a deacylase, and plays an important role in leucine metabolism and insulin secretion [4].”
BackgroundQiao, Y.-N., Li, L., Hu, S.-H., Yang, Y.-X., Ma, Z., Huang, L., An, Y., Yuan, Y., Lin, Y., Xu, W., et al. (2024) · Cell Discovery · doi:10.1038/s41421-023-00636-x · Cited by 95
“Therefore, in addition to its ADP-ribosyltransferase 30 , lipoamidase 55 and deacylase 56 activities, the newly identi fi ed de-carbamylase activity of SIRT4 31 expands its roles in glutamate and GABA metabolism and neuronal activity regulation.”
BackgroundChiral Posttranslational Modification to Lysine ε-Amino Groups
Moreno-Yruela, C., Bæk, M., Monda, F., & Olsen, C. A. (2022) · Accounts of Chemical Research · doi:10.1021/acs.accounts.2c00115 · Cited by 85
Self-citationSirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster
Wood, J. G., Schwer, B., Wickremesinghe, P. C., Hartnett, D. A., Burhenn, L., Garcia, M., Li, M., Verdin, E. M., & Helfand, S. L. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720673115 · Cited by 83
“In addition to lipids, branched-chain amino acids (BCAAs) can be oxidized in the mitochondria to provide fuel during fasting, and mammalian SIRT4 has been implicated in regulation of this pathway (13).”
BackgroundSirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer
Tomaselli, D., Steegborn, C., Mai, A., & Rotili, D. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00474 · Cited by 80
“Important metabolic intermediates in this process are also HMG-CoA and MG-CoA (16) that, together with G-CoA, MGcCoA, and other acyl-CoA, seem able to spontaneously acylate and destabilize the MCC itself, reducing leucine flux through the branched chain amino acid catabolic pathway (15) (Figure 1).”
BackgroundInfluentialBetsinger, C. N., & Cristea, I. M. (2019) · Journal of Proteome Research · doi:10.1021/acs.jproteome.9b00086 · Cited by 84
Sirtuins in Metabolic and Epigenetic Regulation of Stem Cells
Fang, Y., Tang, S., & Li, X. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.12.002 · Cited by 79
Rajabi, N., Auth, M., Troelsen, K. R., Pannek, M., Bhatt, D. P., Fontenas, M., Hirschey, M. D., Steegborn, C., Madsen, A. S., & Olsen, C. A. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201709050 · Cited by 76
Self-citationUncoupling mechanism and redox regulation of mitochondrial uncoupling protein 1 (UCP1)
Ježek, P., Jabůrek, M., & Porter, R. K. (2018) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2018.11.007 · Cited by 73
“enzymes associated with leucine metabolism [81].”
Mitochondrial Sirtuins in Reproduction
Emidio, G. D., Falone, S., Artini, P. G., Amicarelli, F., D’Alessandro, A. M., & Tatone, C. (2021) · Antioxidants · doi:10.3390/antiox10071047 · Cited by 74
The Role of Sirtuins in Kidney Diseases
Hong, Y. A., Kim, J. E., Jo, M.-J., & Ko, G.-J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186686 · Cited by 74
“SIRT4 is also a lysine deacetylase and can remove multiple derivatives of methylglutaryl from lysine residues to regulate leucine metabolism [49].”
BackgroundDing, X.-W., Robinson, M., Li, R., Aldhowayan, H., Geetha, T., & Babu, J. R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105783 · Cited by 73
A global view of the human post-translational modification landscape
Kitamura, N., & Galligan, J. J. (2023) · Biochemical Journal · doi:10.1042/bcj20220251 · Cited by 81
Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection
Fabbrizi, E., Fiorentino, F., Carafa, V., Altucci, L., Mai, A., & Rotili, D. (2023) · Cells · doi:10.3390/cells12060852 · Cited by 77
“In detail, SIRT4 can remove glutaryl, 3-methylglutaryl, 3-hydroxy-3-methyl-glutaryl (HMG), and 3-methylglutaconyl groups [39,40].”
Keeping the balance in NAD metabolism
Strømland, Ø., Niere, M., Nikiforov, A. A., VanLinden, M. R., Heiland, I., & Ziegler, M. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180417 · Cited by 73
Updates on the epigenetic roles of sirtuins
Kosciuk, T., Wang, M., Hong, J. Y., & Lin, H. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.01.023 · Cited by 73
Extranuclear Sirtuins and Metabolic Stress
Elkhwanky, M., & Hakkola, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7270 · Cited by 67
“Repression of SIRT3 by high-fat diet and diabetes is probably involved in the metabolic disturbances. hydroxymethylglutaryl (HMG)-lysine, and 3-methylglutaconyl (MGc)-lysine (2, 121).”
InfluentialTherapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5
Fiorentino, F., Castiello, C., Mai, A., & Rotili, D. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00687 · Cited by 70
Wang, Y., Yang, H., Geerts, C., Fürtös, A., Waters, P. J., Cyr, D., Wang, S., & Mitchell, G. A. (2022) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2022.106966 · Cited by 74
Costa‐Machado, L. F., & Fernández-Marcos, P. J. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1634953 · Cited by 66
“SIRT4 has been shown to ADPribosylate [158], deacetylate [159], deacylate [160] or delipoylate [161] different targets including glutamate dehydrogenase, malonyl CoA decarboxylase or pyruvate dehydrogenase, affecting crucial metabolic pathways.”
BackgroundSIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis
Zaganjor, E., Yoon, H., Spinelli, J. B., Nunn, E. R., Laurent, G., Keskinidis, P., Sivaloganathan, S., Joshi, S., Notarangelo, G., Mulei, S., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109345 · Cited by 66
“However, on a high-fat diet (HFD) challenge, SIRT4 KO mice are protected from weight gain but are more insulin resistant (Anderson et al., 2017; Laurent et al., 2013b; Zaganjor et al., 2017).”
BackgroundSIRT4 and Its Roles in Energy and Redox Metabolism in Health, Disease and During Exercise
Han, Y., Zhou, S., Coetzee, S., & Chen, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01006 · Cited by 72
Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis
Yin, X., Peng, J., Gu, L., Liu, Y., Li, X., Wu, J., Xu, B., Zhuge, Y., & Zhang, F. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05409-0 · Cited by 75
“SIRT4 is involved in physiological processes such as energy metabolism [7], insulin secretion [8], and fatty acid oxidation [9].”
BackgroundSirtuin 4 activates autophagy and inhibits tumorigenesis by upregulating the p53 signaling pathway
Li, J., Zhan, H., Ren, Y., Feng, M., Wang, Q., Jiao, Q., Wang, Y., Liu, X., Zhang, S., Du, L., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01063-3 · Cited by 63
“Recent studies have demonstrated that SIRT4 knockout (KO) mice have increased insulin secretion and ultimately glucose tolerance and insulin resistance [24, 25], all of which are high-risk factors for PDAC, suggesting that SIRT4 is closely associated with PDAC.”
BackgroundXu, H. M., Liu, Y., Li, L.-S., & Liu, Y. (2023) · Aging and Disease · doi:10.14336/ad.2022.1123 · Cited by 69
“SIRT4 is composed of a homologous sirtuin deacylase domain, a conserved catalytic histidine (H161), and a NAD-binding region [22].”
BackgroundKasai, S., Kokubu, D., Mizukami, H., & Itoh, K. (2023) · Biomolecules · doi:10.3390/biom13101544 · Cited by 75
“Importantly, Sirt4 is a specific lysine deacylase that catalyzes MCC deacylation and activates MCCC2 to enhance leucine catabolism [36].”
BackgroundSIRT4 is the last puzzle of mitochondrial sirtuins
Li, Y., Zhou, Y., Wang, F., Chen, X., Wang, C., Wang, J., Liu, T., Li, Y., & He, B. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.07.031 · Cited by 63
The balance between NAD+ biosynthesis and consumption in ageing
Strømland, Ø., Diab, J., Ferrario, E., Sverkeli, L. J., & Ziegler, M. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111569 · Cited by 64
The Emerging Role of HDACs: Pathology and Therapeutic Targets in Diabetes Mellitus
Dewanjee, S., Vallamkondu, J., Kalra, R. S., Chakraborty, P., Gangopadhyay, M., Sahu, R., Medala, V. K., John, A. A., Reddy, P. H., Feo, V. D., et al. (2021) · Cells · doi:10.3390/cells10061340 · Cited by 63
“SIRT4 has also been revealed to remove three acyl moieties, such as methylglutaryl, hydroxymethylglutaryl, and 3-methylglutaconyl from lysine residues and impede insulin secretion by controlling leucine metabolism [107].”
BackgroundMetabolic sensing and control in mitochondria
Liu, Y., & Birsoy, K. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.02.016 · Cited by 65
Reactive Acyl-CoA Species Modify Proteins and Induce Carbon Stress
Trub, A. G., & Hirschey, M. D. (2018) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2018.02.002 · Cited by 60
Self-citationCirculating Branched Chain Amino Acids and Cardiometabolic Disease
Fine, K. S., Wilkins, J. T., & Sawicki, K. T. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.031617 · Cited by 67
“19 For a full discussion of BCAA uptake, catabolism, signaling, and regulation, we refer the reader to several excellent reviews.”
BackgroundAdvances in the Development of Therapeutics for Cytomegalovirus Infections
Acosta, E. P., Bowlin, T. L., Brooks, J., Chiang, L. W., Hussein, I. T. M., Kimberlin, D. W., Kauvar, L. M., Leavitt, R. Y., Prichard, M. N., & Whitley, R. J. (2019) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiz493 · Cited by 60
“In addition to the deacetylase activity of all 7 SIRTs, SIRT4, SIRT5, and SIRT6 can also remove lipoyl, methylglutaryl, hydroxymethylglutaryl, and 3-methylglutaconyl moieties [106, 107]; malonyl and succinyl moieties; and myristoyl moieties, respectively.”
BackgroundCurrent Trends in Sirtuin Activator and Inhibitor Development
Bursch, K. L., Goetz, C. J., & Smith, B. C. (2024) · Molecules · doi:10.3390/molecules29051185 · Cited by 60
“All mammals, including humans, express seven sirtuin isoforms (Sirt1-7) [5] that comprise the class III histone deacetylase (HDAC) family [9] and display diverse subcellular localization, deacylase activities, and protein targets [10,11].”
BackgroundNAD(H) in mitochondrial energy transduction: implications for health and disease
Walker, M. A., & Tian, R. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2018.03.011 · Cited by 59
Molecular and cellular regulatory roles of sirtuin protein
Pande, S., & Raisuddin, S. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2070722 · Cited by 58
“Most recently its lysine deacylase activity has been reported (Anderson et al. 2017) but awaits validation.”
BackgroundSirtuin Modulators: Past, Present, and Future Perspectives
Fiorentino, F., Mautone, N., Menna, M., D’Acunzo, F., Mai, A., & Rotili, D. (2022) · Future Medicinal Chemistry · doi:10.4155/fmc-2022-0031 · Cited by 57
Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
Sandonà, M., Cavioli, G., Renzini, A., Cedola, A., Gigli, G., Coletti, D., McKinsey, T. A., Moresi, V., & Saccone, V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054306 · Cited by 58
Tanabe, K., Liu, J., Kato, D., Kurumizaka, H., Yamatsugu, K., Kanai, M., & Kawashima, S. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-21060-2 · Cited by 53
A Molecular Perspective on Sirtuin Activity
Teixeira, C. S. S., Cerqueira, N. M. F. S. A., Gomes, P., & Sousa, S. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228609 · Cited by 57
The Mystery of Extramitochondrial Proteins Lysine Succinylation
Chinopoulos, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116085 · Cited by 55
“SIRT1, SIRT2, and SIRT3 are deacetylases; SIRT4, which was originally demonstrated to be an ADP-ribosyltransferase and lipoamidase [78] is a demethylglutarylase, dehydroxymethylglutarylase, and demethylglutaconylase [79]; SIRT5 is a robust desuccinylase [80]; SIRT6 has weak deacetylase activity, but more efficient dea…”
Background3-Methylglutaric acid in energy metabolism
Jones, D. E., Perez, L., & Ryan, R. O. (2019) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.11.006 · Cited by 54
Targeting Sirtuins: Substrate Specificity and Inhibitor Design
Rajabi, N., Galleano, I., Madsen, A. S., & Olsen, C. A. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.003 · Cited by 52
Self-citationSirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer
Huang, G., & Zhu, G. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s157724 · Cited by 53
“10 In addition to the regulatory role in metabolism, SIRT4 was found to have other activities.”
Ustilaginoidea virens modulates lysine 2‐hydroxyisobutyrylation in rice flowers during infection
Chen, X., Xu, Q., Duan, Y., Liu, H., Chen, X., Huang, J., Luo, C., Zhou, D., & Zheng, L. (2021) · Journal of Integrative Plant Biology · doi:10.1111/jipb.13149 · Cited by 50
Cellular and molecular biology of sirtuins in cardiovascular disease
Liu, Y., Wen, R., Liu, C., Zhang, T., & Yang, N. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114931 · Cited by 53
Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease
Wang, R., Sun, H., Wang, G., & Ren, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197182 · Cited by 51
“For example, SIRT5 exerts the activity of desuccinylase, demalonylase, and deglutarylase [37]; SIRT4 removes the acyl moieties from lysine residues such as methylglutaryl-, hydroxymethylglutaryland 3-methylglutaconyl-lysine [38]; SIRT6 functions to deacetylate long-chain fatty acyl groups rather than protein deacetyla…”
BackgroundNebbioso, M., Lambìase, A., Armentano, M., Tucciarone, G., Sacchetti, M., Greco, A., & Alisi, L. (2021) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2021.04.003 · Cited by 53
Pathways of Non-enzymatic Lysine Acylation
Baldensperger, T., & Glomb, M. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.664553 · Cited by 47
“The corresponding acylation modifications are regulators of leucine metabolism and insulin secretion (Anderson et al., 2017).”
BackgroundInfluentialEmerging Roles of SIRT3 in Cardiac Metabolism
Murugasamy, K., Munjal, A., & Sundaresan, N. R. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.850340 · Cited by 48
Meyer, J. G., Softic, S., Basisty, N., Rardin, M. J., Verdin, E. M., Gibson, B. W., Ilkayeva, O., Newgard, C. B., Kahn, C. R., & Schilling, B. (2018) · PLoS ONE · doi:10.1371/journal.pone.0208973 · Cited by 52
Self-citationRoles of sirtuin family members in chronic obstructive pulmonary disease
Zhang, X.-Y., Li, W., Zhang, J., Li, C., Zhang, J., & Lv, X. (2022) · Respiratory Research · doi:10.1186/s12931-022-01986-y · Cited by 50
“SIRT4 has ADP-ribosyltransferase [78], lipoamidase [81], deacylase [82], and substrate-specific deacetylase [83] activity.”
Epigenetic Remodeling in Obesity-Related Vascular Disease
Masi, S., Ambrosini, S., Mohammed, S. A., Sciarretta, S., Lüscher, T. F., Paneni, F., & Costantino, S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8040 · Cited by 49
“…to an increase in fatty acid oxidation and lipid metabolism (106, 168, 210) These findings were confirmed by other studies where SIRT4 deletion was found to increase both basal and stimulated insulin secretion, ultimately resulting in the development of insulin resistance and glucose intolerance (8).”
Role of Sirtuins in Tumor Angiogenesis
Edatt, L., Poyyakkara, A., Raji, G. R., Ramachandran, V., Shankar, S. S., & Kumar, V. B. S. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01516 · Cited by 43
“In addition, a number of non-histone proteins like nuclear factor-κB (NFκB), forkhead box type O transcription factors (FOXO), peroxisome proliferator-activated receptor g (PPARg), coactivator 1α (PGC-1α), enzymes like acetyl coenzyme A (CoA) synthetase 2 (AceCS2), and structural proteins, such as α-tubulin are also d…”
BackgroundInfluentialShaw, E., Talwadekar, M., Rashida, Z., Mohan, N., Acharya, A., Khatri, S., Laxman, S., & Kolthur‐Seetharam, U. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00212-19 · Cited by 42
“Although reports have shown that it has ADP-ribosyltransferase (21, 22) and NAD -dependent deacylase activities (23, 24), the robust catalytic activity, as well as the biological functions, of SIRT4 is largely unknown.”
BackgroundPotent and Selective Inhibitors of Human Sirtuin 5
Kalbas, D., Liebscher, S., Nowak, T., Meleshin, M., Pannek, M., Popp, C., Alhalabi, Z., Bordusa, F., Sippl, W., Steegborn, C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01648 · Cited by 42
Continuous Activity Assay for HDAC11 Enabling Reevaluation of HDAC Inhibitors
Kutil, Z., Mikešová, J., Zessin, M., Meleshin, M., Nováková, Z., Alquicer, G., Kozikowski, A. P., Sippl, W., Bařinka, C., & Schutkowski, M. (2019) · ACS Omega · doi:10.1021/acsomega.9b02808 · Cited by 40
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
