Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases

Wagner, Gregory R.; Hirschey, Matthew D.

doi:10.1016/j.molcel.2014.03.027

Cited by 292 publications

(302 citation statements)

References 101 publications

(140 reference statements)

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“…It has been proposed that protein acylation results from the nonenzymatic lysine modification (167), due to accumulation of intrinsically reactive carbon metabolites, which can negatively impact protein function and, hence, disrupt cellular homeostasis (166). Therefore, by removing these lysine PTMs, sirtuins may contribute to maintaining the quality of the proteome, especially in mitochondria.…”

Section: Sirt5 and Protein Deacylationmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

133

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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Section: Sirt5 and Protein Deacylationmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

133

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“…For example, dysregulation of malonyl-CoA is associated with diseases, such as ischemic heart disease and diabetes (35,36). Additionally, these short-chain CoAs are thermodynamically favorable for their corresponding lysine acylation reactions (37). Further, these CoAs are structurally similar to acetyl-CoA, leading to apparent enzymatically catalyzed acylation by promiscuous acetyltransferases.…”

mentioning

confidence: 99%

“…Future Studies-A major question remaining in the field is the mechanism by which lysine acylation occurs (for a recent review, see ref (37)). No acyltransferases have been shown to catalyze the transfer of malonyl-, succinyl-, or glutaryl-modifications to proteins in vivo, although this can be performed using a truncated p300 acetyltransferase in vitro (29).…”

mentioning

confidence: 99%

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation

Hirschey

Zhao

2015

Molecular & Cellular Proteomics

365

311

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Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases. Molecular & Cellular

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“…It is also possible that succinylation of amino groups in the proteome and lipidome may be the result of nonenzymatic reactions due to the fact that cells maintain a pool of succinyl-coenzyme A that can spontaneously cause succinylation of amino groups and other nucleophilic groups such as a thiol group. If this is true, cells must be equipped with hydrolases such as sirtuins to reverse such nonenzymatic modification [26]. Except for Nsuccinyl-lysyl-PG, we did not observe any anionic species that would match the expected fragmentation pattern of analogous N-acetyl-lysyl-PG, N-malonyl-lysyl-PG, or N-glutaryl-lysyl-PG.…”

Section: Resultsmentioning

confidence: 70%

Characterization of N-Succinylation of L-Lysylphosphatidylglycerol in Bacillus subtilis Using Tandem Mass Spectrometry

Atila

Katselis

Chumala

et al. 2016

J. Am. Soc. Mass Spectrom.

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Abstract. Phospholipids generally dominate in bacterial lipids. The negatively charged nature of phospholipids renders bacteria susceptible to cationic antibiotic peptides. In comparison with Gram-negative bacteria, Gram-positive bacteria in general have much less zwitterionic phosphatidylethanolamine. However, they are known for producing aminoacylated phosphatidylglycerol (PG), especially positively charged L-lysyl-PG, which is catalyzed by lysyl-PG synthase MprF, which appears to have a broad range of specificity for L-aminoacyl transfer RNAs. In addition, many Gram-positive bacteria also have a dlt-gene-coded D-alanylation pathway for lipoteichoic acids and wall teichoic acids covalently attached to a glycolipid or peptidoglycan. D-Alanylation also masks the dominant negative charge of the phosphate-rich polymers of teichoic acids. Using mass spectrometry, we have recently observed that precursor scans in negative mode for deprotonated amino acid fragments were most sensitive for ester-linked amino acids. Such a scan for precursors generating an m/z 145 lysyl anion revealed lysyl-PG as well as an additional species 100 m/z units greater than lysyl-PG. This unexpected species corresponded precisely to the expected mass of Nsuccinylated lysyl-PG. Tandem mass spectrometry revealed a precise match to the fragmentation pattern of this putative new species. PG, lysyl-PG, and N-succinyl-lysyl-PG may form a complete loop of charge reversal from -1 to +1 and then back to -1. Analogous charge reversal by N-succinylation of lysine residues in the bacterial as well as eukaryotic proteomes has been recently discovered as a major posttranslational modification. Such modification in bacterial lipids is possibly catalyzed by an enzyme homologous to the enzymes that modify lysine residues in proteins.

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Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases

Cited by 292 publications

References 101 publications

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation

Characterization of N-Succinylation of L-Lysylphosphatidylglycerol in Bacillus subtilis Using Tandem Mass Spectrometry

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