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Review
. 2014 Apr 10;54(1):5-16.
doi: 10.1016/j.molcel.2014.03.027.

Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases

Gregory R Wagner  1 , Matthew D Hirschey  2
Affiliations
Review

Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases

Gregory R Wagner et al. Mol Cell. .

Abstract

Cellular proteins are decorated with a wide range of acetyl and other acyl modifications. Many studies have demonstrated regulation of site-specific acetylation by acetyltransferases and deacetylases. Acylation is emerging as a new type of lysine modification, but less is known about its overall regulatory role. Furthermore, the mechanisms of lysine acylation, its overlap with protein acetylation, and how it influences cellular function are major unanswered questions in the field. In this review, we discuss the known roles of acetyltransferases and deacetylases and the sirtuins as a conserved family of a nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacylases that are important for response to cellular stress and homeostasis. We also consider the evidence for an emerging idea of nonenzymatic protein acylation. Finally, we put forward the hypothesis that protein acylation is a form of protein "carbon stress" that the deacylases evolved to remove as a part of a global protein quality-control network.

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Figures

Figure 1
Figure 1. Model of sirtuin-mediated protein quality control
(A) Intrinsically reactive metabolites can non-enzymatically react with nucleophilic protein residues to form post-translational modifications which can compromise protein function and could be considered “carbon stress”. (B) Non-enzymatic acyl-modifications can be targeted for removal by the sirtuin family of NAD+-dependent lysine deacylases to restore protein function and cellular health, which is part of a global protein quality control system.
Figure 2
Figure 2. The reactivity of functional groups in biology
(A) (Left) Carbonyl-containing functional groups commonly used in biological systems are ranked according to their inherent reactivity. (Right) Specific examples of cellular metabolites containing the select carbonyl compounds are listed along with the biological processes in which they are generated or consumed. Carbonyl groups are highlighted in blue and leaving groups are highlighted in red. (B) Reactive acyl-containing metabolites and the mechanisms leading to non-enzymatic protein modification. AGE, advanced glycation end products.
Figure 3
Figure 3. Sirtuin-mediated deacetylation is analogous to other protein quality control mechanisms
(A) Reactive acetyl-CoA is predicted to increase in mice undergoing calorie restriction, which is correlated with hyperacetylation of mitochondrial proteins. In this setting, the mitochondrial deacetylase SIRT3 maintains the acetylation status of select protein lysine residues at low levels, thereby maintaining protein function and metabolic health (Hebert et al., 2013). (B) During the stationary phase in bacteria, the concentration of reactive acetyl-phosphate increases which is correlated with hyperacetylation of proteins. The bacterial sirtuin deacetylase CobB also regulates the acetylation status of select lysines residues at low levels, which likely serves to maintain protein function and metabolic homeostasis (Weinert et al., 2013b). In an analogous manner, oxidative stress and nitrosative stress cause the oxidation (C) and nitrosylation (D) of protein residues, respectively. These damaging non-enzymatic protein modifications are removed by methionine sulfoxide reductases (MsrA,B) and thioredoxins (Trx) or the S-nitrosoglutathione reductase (GSNOR) system, which preserve protein function and support cellular health.
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References

    1. Albaugh BN, Arnold KM, Denu JM. KAT(ching) metabolism by the tail: insight into the links between lysine acetyltransferases and metabolism. Chembiochem : a European journal of chemical biology. 2011;12:290–298. - PMC - PubMed
    1. Allfrey VG, Faulkner R, Mirsky AE. Acetylation And Methylation Of Histones And Their Possible Role In The Regulation Of RNA Synthesis. Proc Natl Acad Sci U S A. 1964;51:786–794. - PMC - PubMed
    1. Baddiley J, Kekwick RA, Thain EM. A new method for acetylating proteins. Nature. 1952;170:968–970. - PubMed
    1. Bharathi SS, Zhang Y, Mohsen AW, Uppala R, Balasubramani M, Schreiber E, Uechi G, Beck ME, Rardin MJ, Vockley J, et al. SIRT3 Regulates Long-chain Acyl-CoA Dehydrogenase by Deacetylating Conserved Lysines Near the Active Site. The Journal of biological chemistry. 2013 - PMC - PubMed
    1. Brown K, Xie S, Qiu X, Mohrin M, Shin J, Liu Y, Zhang D, Scadden DT, Chen D. SIRT3 reverses aging-associated degeneration. Cell Rep. 2013;3:319–327. - PMC - PubMed

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