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
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“It also interacts with sirtuin 4 (SIRT4) and may mediate its physiology 29,30 .”
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“SIRT4, on the other hand, catalyzes weak ADP-ribosyl transfer (Du et al., 2009) and lipoamidase activity (Anderson et al., 2017).”
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“…study indicated that three leucine catabolic intermediates, methylglutaryl-(MG), hydroxymethyl - glutaryl-(HMG), and 3-methylglutaconyl-(MGc)-lysine, can modify enzymes involved in branched-chain amino acid (BCAA) metabolism to inhibit their activity, form - ing a negative feedback loop [86 ].”
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“184 Before oxidation by BCKDH, α -keto acids can be reduced to branched α -hydroxyketo acids, 185,186 which are directly degraded by α -hydroxyketo acid oxidase in the liver and are undetectable in the urine of healthy adults.”
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Self-citationBindingDB (2025) · UC San Diego · doi:10.7270/q29w0m52
BindingDB Entry 50008380: Cyclic tripeptide-based potent human SIRT7 inhibitors.
BindingDB (2021) · UC San Diego · doi:10.7270/q20v8h65
BindingDB (2023) · UC San Diego · doi:10.7270/q2125xq3
BindingDB Entry 50000621: Potent and Selective Inhibitors of Human Sirtuin 5.
BindingDB (2019) · UC San Diego · doi:10.7270/q2ww7m4j
What are the potentials of the different sirtuin proteins as therapeutic targets?
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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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