Non-enzymatic N-acetylation of lysine residues by acetylCoA often occurs via a proximal S-acetylated thiol intermediate sensitive to glyoxalase II
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Acetyl coenzyme A (AcCoA), a key intermediate in mitochondrial metabolism, N-acetylates lysine residues, disrupting and, in some cases, regulating protein function. The mitochondrial lysine deacetylase Sirtuin 3 (Sirt3) reverses this modification with benefits reported in diabetes, obesity, and aging. We show that non-enzymatic lysine N-acetylation by AcCoA is greatly enhanced by initial acetylation of a cysteine residue, followed by SN-transfer of the acetyl moiety to a nearby lysine on mitochondrial proteins and synthetic peptides. The frequent occurrence of an S-acetyl intermediate before lysine N-acetylation suggests that proximity to a thioester is a key determinant of lysine susceptibility to acetylation. The thioesterase glyoxalase II (Glo2) can limit protein S-acetylation, thereby preventing subsequent lysine N-acetylation. This suggests that the hitherto obscure role of Glo2 in mitochondria is to act upstream of Sirt3 in minimizing protein N-acetylation, thus limiting protein dysfunction when AcCoA accumulates.
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Proximity to thiols such as cysteine residues increases the rate of acylation for nearby lysines.
“As an added twist on semi-enzymatic acylation, proximity to thiols such as those provided by cysteine residues apparently increases the rate of acylation for nearby lysines (James et al. 2017).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as James et al. 2017
The thiol-proximity mechanism affects both acetylation and succinylation.
“This mechanism has been shown to affect both acetylation and succinylation; other acylation modifications are likely to be similarly affected.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as James et al. 2017
A recent study showed that thiols can undergo spontaneous acetylation, providing a route to lysine modification.
“A recent study demonstrated spontaneous acetylation of thiols as a pathway towards lysine modification ((James et al. 2017)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as James et al. 2017
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References 22 · Cited by 112
- Authors
- James, A. M., Hoogewijs, K., Logan, A., Hall, A. R., Ding, S., Fearnley, I. M., & Murphy, M. P.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- James, Andrew M.
- Murphy, Michael P.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 18
- Issue
- 9
- Pages
- 2105-2112
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6381604
- OpenAlex
- W2592360697
- Cited by
- 112
- References
- 22
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 12 · 2023: 17 · 2022: 22 · 2021: 8 · 2020: 14 · 2019: 12 · 2018: 14 · 2017: 2
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Medical Research Council (MC_U105663142)
- Wellcome Trust (110159/Z/15/Z)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- acetyl-CoA, thioester intermediate, glyoxalase II, SIRT3, lysine deacetylases, mitochondrial proteins, thioesterase, protein acetylation, mitochondrial metabolism
- MeSH terms
- Hydroxyacylglutathione Hydrolase, Acetyl Coenzyme A, Acetylation, Cysteine, Humans, Lysine, Mitochondria, Recombinant Proteins, Sulfhydryl Compounds, Thiolester Hydrolases, Mitochondrial Proteins, Sirtuin 3, Fatty Acid Synthases
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