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.
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“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
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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 3,440 · 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
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]”
Background
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
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