Key Points
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Acetylation is a key post-translational modification that integrates metabolic flux and physiological processes within cells, including circadian rhythm, cell cycle and energy production
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Lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) are responsible for reversible changes in protein acetylation status
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Metabolites or cofactors, including nicotinamide adenine dinucleotide (NAD+), nicotinamide, coenzyme A, acetyl coenzyme A, zinc and butyrate and/or β-hydroxybutyrate, directly alter KAT or KDAC activity to link energy status with cellular and organismal homeostasis
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The association between NAD+ and sirtuin-mediated mitochondrial improvements is clinically relevant, but the translational potential between other metabolites and cofactors and acetylation and/or deactylation reactions is less clear
Abstract
Reversible acetylation was initially described as an epigenetic mechanism regulating DNA accessibility. Since then, this process has emerged as a controller of histone and nonhistone acetylation that integrates key physiological processes such as metabolism, circadian rhythm and cell cycle, along with gene regulation in various organisms. The widespread and reversible nature of acetylation also revitalized interest in the mechanisms that regulate lysine acetyltransferases (KATs) and deacetylases (KDACs) in health and disease. Changes in protein or histone acetylation are especially relevant for many common diseases including obesity, diabetes mellitus, neurodegenerative diseases and cancer, as well as for some rare diseases such as mitochondrial diseases and lipodystrophies. In this Review, we examine the role of reversible acetylation in metabolic control and how changes in levels of metabolites or cofactors, including nicotinamide adenine dinucleotide, nicotinamide, coenzyme A, acetyl coenzyme A, zinc and butyrate and/or β-hydroxybutyrate, directly alter KAT or KDAC activity to link energy status to adaptive cellular and organismal homeostasis.
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Acknowledgements
K.J.M. is the recipient of a Heart and Stroke Foundation of Canada research fellowship award. H.Z. is supported by scholarships from the China Scholarship Council and CARIGEST SA. E.K. is supported by the Fondation Romande pour la Recherche sur le Diabète, Switzerland. J.A. is the Nestlé Chair in Energy Metabolism at École Polytechnique Fédéral de Lausanne. Work in the laboratory is supported by the École Polytechnique Fédérale de Lausanne, the National Institutes of Health (R01AG043930), the Swiss National Science Foundation (31003A-124713) and Systems X (51RTP0-151019), and Krebsforschung Schweiz (KFS-3082-02-2013).
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K.J.M., H.Z. and E.K. contributed equally to this article. K.J.M., H.Z. and E.K. researched data for the article and wrote the manuscript. All authors made substantial contribution to discussion of the content and reviewed/edited the manuscript before submission.
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Supplementary information
Supplementary Table 1
The cellular location, activity, targets and null phenotype of lysine acetyltransferases. (DOCX 57 kb)
Supplementary Table 2
The cellular location, activity, targets and null phenotype of lysine deactelyases. (DOCX 87 kb)
Supplementary Table 3
The enzyme activity of class I, II and IV subfamily of lysine deactelyases. (DOCX 26 kb)
Supplementary Figure 1
Mechanism of nonenzymatic acetylation. The reaction starts with a nucleophilic attack of the carbonyl carbon of an acetyl-CoA molecule’s acetyl group by the positively charged ɛ-amino group of lysine. This leads to formation of an unstable intermediate, which then, by displacing the thioester bond, leaves an acetylated lysine and CoA. Abbreviation: CoA, coenzyme A. (PDF 5804 kb)
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Menzies, K., Zhang, H., Katsyuba, E. et al. Protein acetylation in metabolism — metabolites and cofactors. Nat Rev Endocrinol 12, 43–60 (2016). https://doi.org/10.1038/nrendo.2015.181
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DOI: https://doi.org/10.1038/nrendo.2015.181
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