Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2
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We report that human acetyl-CoA synthetase 2 (AceCS2) is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at Lys-642 in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys-642 both in vitro and in vivo . Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. This report identifies the first acetylated substrate protein of SIRT3. Our findings show that a mammalian sirtuin directly controls the activity of a metabolic enzyme by means of reversible lysine acetylation. Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans.
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SIRT3 deacetylates and activates acetyl-CoA synthetase 2 at K642 in the human protein or K635 in mice.
“SIRT3 also deacetylates (at K642 in the human protein or K635 in mice) and activates acetyl-CoA synthetase 2, an enzyme in extrahepatic tissues that activates acetate into acetyl-CoA ((Schwer et al. 2006); (Hallows, Lee, and Denu 2006)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Schwer et al. 2006
SIRT3 deacetylates AceCS2 and thereby reactivates its conversion of acetate into acetyl-CoA.
“SIRT3-mediated deacetylation of AceCS2 reactivates the enzyme.”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Schwer et al., 2006
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Hirschey, M. D., Shimazu, T., Huang, J., & Verdin, E. (2009) · Methods in Enzymology · doi:10.1016/s0076-6879(09)05008-3 · Cited by 55 · see citing works
Self-citationEvidence supporting a mechanistic role of sirtuins in mood and metabolic disorders
Alageel, A., Tomasi, J., Tersigni, C., Brietzke, E., Zuckerman, H., Subramaniapillai, M., Lee, Y., Iacobucci, M., Rosenblat, J. D., Mansur, R. B., et al. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.05.017 · Cited by 45 · see citing works
- Authors
- Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S., & Verdin, E.
- Affiliations
- University of California, San Francisco (US)
- University of Southern Denmark (DK)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-07-05
- Volume
- 103
- Issue
- 27
- Pages
- 10224-10229
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1502439
- OpenAlex
- W2075747312
- Cited by
- 705
- References
- 38
- Citations by year
- 2026: 9 · 2025: 29 · 2024: 26 · 2023: 17 · 2022: 25 · 2021: 31 · 2020: 21 · 2019: 34 · 2018: 39 · 2017: 36 · 2016: 46 · 2015: 42 · 2014: 34 · 2013: 44 · 2012: 62
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- acetyl-CoA synthetase 2, lysine acetylation, SIRT3, enzyme activation, mitochondrial matrix proteins, metabolic regulation
- MeSH terms
- Acetate-CoA Ligase, Acetylation, Amino Acid Sequence, Animals, Binding Sites, Cell Line, Chlorocebus aethiops, Humans, Lysine, Mitochondria, Molecular Sequence Data, Sequence Alignment, Conserved Sequence, Mitochondrial Proteins, Sirtuins, Sirtuin 3
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