A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation
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The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive intermediates that non-enzymatically modify proteins. Based on this mechanism, we predicted, validated, and characterized a protein modification: 3-hydroxy-3-methylglutaryl(HMG)-lysine. In a model of altered HMG-CoA metabolism, we found evidence of two additional protein modifications: 3-methylglutaconyl(MGc)-lysine and 3-methylglutaryl(MG)-lysine. Using quantitative proteomics, we compared the "acylomes" of two reactive acyl-CoA species, namely HMG-CoA and glutaryl-CoA, which are generated in different pathways. We found proteins that are uniquely modified by each reactive metabolite, as well as common proteins and pathways. We identified the tricarboxylic acid cycle as a pathway commonly regulated by acylation and validated malate dehydrogenase as a key target. These data uncover a fundamental relationship between reactive acyl-CoA species and proteins and define a new regulatory paradigm in metabolism.
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Divalent acyl-CoAs such as succinyl-CoA and glutaryl-CoA can use the anhydride route to acylate lysines faster than monovalent acyl-CoAs such as acetyl-CoA.
“Divalent acyl groups such as succinyl- and glutaryl-CoA can use this alternative non-enzymatic reaction mechanism to achieve higher reaction rates than monovalent acyl species such as acetyl-CoA.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Wagner et al. 2017
Some acyl-CoA species can modify lysine residues through a cyclic anhydride intermediate.
“Recent work has further shown that some acyl-CoA species can modify lysines via a cyclic anhydride intermediate (Wagner et al. 2017).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Wagner et al. 2017
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- Authors
- 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., Grimsrud, P. A., & Hirschey, M. D.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- University of Colorado Anschutz (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Corresponding author
- Hirschey, Matthew D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 25
- Issue
- 4
- Pages
- 823-837.e8
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5399522
- OpenAlex
- W2604275396
- Cited by
- 258
- References
- 48
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 28 · 2023: 24 · 2022: 37 · 2021: 35 · 2020: 28 · 2019: 19 · 2018: 27 · 2017: 15
- FWCI
- 8.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (2T32DK007012)
- Ellison Medical Foundation
- American Heart Association (12IRG9010008)
- National Institutes of Health
- Canadian Institutes of Health Research (034368-UNC, 178978)
- National Institute on Alcohol Abuse and Alcoholism (R01AA022146)
- Centre hospitalier régional universitaire de Lille
- National Institute on Aging (P30AG028716-01, R01AG045351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- protein acylation, HMG-CoA, glutaryl-CoA, lysine acylation, intramolecular catalysis, TCA cycle, malate dehydrogenase, HMG-CoA reductase inhibition, metabolic regulation
- MeSH terms
- Acyl Coenzyme A, Acylation, Anhydrides, Citric Acid Cycle, Lysine, Mitochondria, Protein Processing, Post-Translational, Proteins, Proteomics, Biocatalysis, Metabolome
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