Sirtuin Lipoamidase Activity Is Conserved in Bacteria as a Regulator of Metabolic Enzyme Complexes

Rowland, Elizabeth A.; Greco, Todd M.; Snowden, Caroline; McCabe, Anne L.; Silhavy, Thomas J.; Cristea, Ileana M.

doi:10.1128/mbio.01096-17

Cited by 33 publications

(52 citation statements)

References 42 publications

(59 reference statements)

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“…A recent report revealed the only known E. coli deacetylase CobB has lipoamidase (delipoylase) activity (47). Lipoyl groups can be found on subunits of several major central metabolic complexes and contribute to the activity of these complexes.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel protein lysine acetyltransferases inEscherichia coli

Christensen

Meyer

Baumgartner

et al. 2018

Preprint

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Post-translational modifications, such as Nε-lysine acetylation, regulate protein function. Nε-lysine acetylation can occur either non-enzymatically or enzymatically. The non-enzymatic mechanism uses acetyl phosphate (AcP) or acetyl coenzyme A (AcCoA) as acetyl donors to modify an Nε-lysine residue of a protein. The enzymatic mechanism uses Nε-lysine acetyltransferases (KATs) to specifically transfer an acetyl group from AcCoA to Nε-lysine residues on proteins. To date, only one KAT (YfiQ, also known as Pka and PatZ) has been identified in E. coli. Here, we demonstrate the existence of 4 additional E. coli KATs: RimI, YiaC, YjaB, and PhnO. In a genetic background devoid of all known acetylation mechanisms (most notably AcP and YfiQ) and one deacetylase (CobB), overexpression of these putative KATs elicited unique patterns of protein acetylation. We mutated key active site residues and found that most of them eliminated enzymatic acetylation activity. We used mass spectrometry to identify and quantify the specificity of YfiQ and the four novel KATs. Surprisingly, our analysis revealed a high degree of substrate specificity. The overlap between KAT-dependent and AcP-dependent acetylation was extremely limited, supporting the hypothesis that these two acetylation mechanisms play distinct roles in the post-translational modification of bacterial proteins. We further showed that these novel KATs are conserved across broad swaths of bacterial phylogeny. Finally, we determined that one of the novel KATs (YiaC) and the known KAT (YfiQ) can negatively regulate bacterial migration. Together, these results emphasize distinct and specific non-enzymatic and enzymatic protein acetylation mechanisms present in bacteria.ImportanceNε-lysine acetylation is one of the most abundant and important post-translational modifications across all domains of life. One of the best-studied effects of acetylation occurs in eukaryotes, where acetylation of histone tails activates gene transcription. Although bacteria do not have true histones, Nε-lysine acetylation is prevalent; however, the role of these modifications is mostly unknown. We constructed an E. coli strain that lacked both known acetylation mechanisms to identify four new Nε-lysine acetyltransferases (RimI, YiaC, YjaB, and PhnO). We used mass spectrometry to determine the substrate specificity of these acetyltransferases. Structural analysis of selected substrate proteins revealed site-specific preferences for enzymatic acetylation that had little overlap with the preferences of the previously reported acetyl-phosphate non-enzymatic acetylation mechanism. Finally, YiaC and YfiQ appear to regulate flagellar-based motility, a phenotype critical for pathogenesis of many organisms. These acetyltransferases are highly conserved and reveal deeper and more complex roles for bacterial post-translational modification.

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Section: Discussionmentioning

confidence: 99%

Identification of novel protein lysine acetyltransferases inEscherichia coli

Christensen

Meyer

Baumgartner

et al. 2018

Preprint

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“…This study did not investigate SIRT4 regulation of the other mitochondrial 2-ketoacid dehydrogenases, but these complexes did associate with SIRT4 in their immunoaffinity purification experiment. Subsequent studies demonstrated that this mechanism was conserved in prokaryotic systems and that OGDH and the glycine cleavage system were also targets of the SIRT4 ortholog, CobB (73). Another study also implicated SIRT4 in regulation of leucine catabolism indicating that BCKDH is likely an additional target of this regulation (74).…”

Section: Lipoic Acid and Ros Generation From Mitochondrial 2-ketoacidmentioning

confidence: 99%

Lipoic acid metabolism and mitochondrial redox regulation

Solmonson

DeBerardinis

2018

Journal of Biological Chemistry

279

255

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Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multienzyme complexes. Many of these dehydrogenases are regulated by reactive oxygen species, mediated through the disulfide bond of the prosthetic lipoyl moiety.Collectively, its functions explain why lipoic acid is required for cell growth, mitochondrial activity and coordination of fuel metabolism.

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“…SIRT4 and SIRT5 have multiple enzymatic activities; for example, SIRT5 cleaves succinyl, malonyl, and glutaryl groups in preference to acetyl groups (360). SIRT4 was shown to have lipoamidase activity that negatively regulates the pyruvate dehydrogenase complex (361,362). Like SIRT3, SIRT4 may contribute to tumor suppression or tumorigenesis depending on conditions.…”

Section: Parp Nad ؉ Metabolism and Inflammationmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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Sirtuin Lipoamidase Activity Is Conserved in Bacteria as a Regulator of Metabolic Enzyme Complexes

Cited by 33 publications

References 42 publications

Identification of novel protein lysine acetyltransferases inEscherichia coli

Identification of novel protein lysine acetyltransferases inEscherichia coli

Lipoic acid metabolism and mitochondrial redox regulation

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

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