Pathways of Non-enzymatic Lysine Acylation

Baldensperger, Tim; Glomb, Marcus A.

doi:10.3389/fcell.2021.664553

Cited by 26 publications

(28 citation statements)

References 99 publications

(130 reference statements)

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“…Zhang et al confirmed lactate as a substrate for N 6 -lactoyl lysine in cell culture via 13 C-label experiments and verified an enzymatically catalyzed acylation via lactoyl-CoA in vitro . Activation of carboxylic acids as the corresponding CoA-thioesters is an important mechanism in physiological systems, and recent research revealed widespread enzymatic and also nonenzymatic lysine acylations through a broad range of acyl-CoA-thioesters . However, in the case of lactoyl-CoA, the enzymatic activation mechanism of lactate is poorly understood.…”

Section: Resultsmentioning

confidence: 99%

“…12 Activation of carboxylic acids as the corresponding CoA-thioesters is an important mechanism in physiological systems, and recent research revealed widespread enzymatic and also nonenzymatic lysine acylations through a broad range of acyl-CoAthioesters. 39 However, in the case of lactoyl-CoA, the enzymatic activation mechanism of lactate is poorly understood. Nevertheless, lactoyl-CoA was quantitated in low amounts of about 0.0172 pmol/g in mouse heart, which was magnitudes lower compared to other CoA derivatives like acetyl-CoA.…”

Section: Determination Of Advanced Glycation End Products In Meatmentioning

confidence: 99%

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Analysis of Glyoxal- and Methylglyoxal-Derived Advanced Glycation End Products during Grilling of Porcine Meat

Eggen

Glomb

2021

J. Agric. Food Chem.

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The reaction of the N 6-amino group of lysine residues and 1,2-dicarbonyl compounds during Maillard processes leads to advanced glycation end products (AGEs). In the present work, we deliver a comprehensive analysis of changes of carbohydrates, dicarbonyl structures, and 11 AGEs during the grilling of porcine meat patties. While raw meat contained mainly glyoxal-derived N 6-carboxymethyl lysine (CML), grilling led to an increase of predominantly methylglyoxal-derived AGEs N 6-carboxyethyl lysine (CEL), N 6-lactoyl lysine, methylglyoxal lysine dimer (MOLD), and methylglyoxal lysine amide (MOLA). Additionally, we identified and quantitated a novel methylglyoxal-derived amidine compound N 1,N 2-di-(5-amino-5-carboxypentyl)-2-lactoylamidine (methylglyoxal lysine amide, MGLA) in heated meat. Analysis of carbohydrates suggested that approximately 50% of the methylglyoxal stemmed from the fragmentation of triosephosphates during the heat treatment. Surprisingly, N 6-lactoyl lysine was the major AGE, and based on model incubations, we propose that approximately 90% must be explained by the nonenzymatic acylation of lysine through S-lactoylglutathione, which was quantitated for the first time in meat herein.

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Section: Resultsmentioning

confidence: 99%

Section: Determination Of Advanced Glycation End Products In Meatmentioning

confidence: 99%

Analysis of Glyoxal- and Methylglyoxal-Derived Advanced Glycation End Products during Grilling of Porcine Meat

Eggen

Glomb

2021

J. Agric. Food Chem.

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“…Previous studies have demonstrated that in vitro incubation of proteins with RACS can give rise to non-enzymatic lysine acylation (Wagner & Payne, 2013;Parks & Escalante-Semerena, 2020;Baldensperger & Glomb, 2021), but the likelihood of lysine modification on a per residue basis in Act2 is largely unexplored. Factors such as local RACS concentrations and protein-protein interactions affecting site accessibility may impact lysine modification in vivo.…”

Section: Crystal Structure Of S Wolfei Göttingen Acetyl-coa Acetyltra...mentioning

confidence: 99%

“…These PTMs have been identified across all domains of life (Verdin & Ott, 2015; VanDrisse & Escalante-Semerena, 2019; Christensen et al, 2019) and have conserved mechanisms of acyl-regulation (Sanders, Jackson & Marmorstein, 2010; Greiss & Gartner, 2009). In eukaryotes, these modifications are primarily found in the mitochondria and are implicated in a wide range of human metabolic-related diseases (Anderson & Hirschey, 2012; Baldensperger & Glomb, 2021; Ali et al, 2018). In prokaryotes, acyl-PTMs modify proteins involved in metabolism in addition to other biological processes such as transcription, chemotaxis, and protein stability (VanDrisse & Escalante-Semerena, 2019; Christensen et al, 2019; Bernal et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Dynamic acylome reveals metabolite driven modifications in Syntrophomonas wolfei

Muroski

Arbing

et al. 2022

Preprint

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Syntrophomonas wolfei is an anaerobic syntrophic microbe that degrades short-chain fatty acids to acetate, hydrogen, and/or formate. This thermodynamically unfavorable process proceeds through a series of reactive acyl-Coenzyme A species (RACS). In other prokaryotic and eukaryotic systems, the production of intrinsically reactive metabolites correlates with acyl-lysine modifications, which have been shown to play a significant role in metabolic processes. Analogous studies with syntrophic bacteria, however, are relatively unexplored and we hypothesize that highly abundant acylations could exist in S. wolfei proteins, corresponding to the RACS derived from degrading fatty acids. Here, by mass spectrometry-based proteomics (LC-MS/MS), we characterize and compare acylome profiles of two S. wolfei subspecies grown on different carbon substrates. Because modified S. wolfei proteins are sufficiently abundant for post-translational modification (PTM) analyses without antibody enrichment, we could identify types of acylations comprehensively, observing six types (acetyl-, butyryl-, 3-hydroxybutyryl-, crotonyl-, valeryl-, hexanyl-lysine), two of which have not been reported in any system previously. All of the acyl-PTMs identified correspond directly to RACS in fatty acid degradation pathways. A total of 369 sites of modification were identified on 237 proteins. Changing the carbon substrate altered the acylation profile. Moreover, structural studies and in vitro acylation assays of a heavily modified enzyme, acetyl-CoA transferase, provided insight on the possible impact of these acyl-protein modifications. Our findings link protein acylation by RACS to shifts in cellular metabolism.

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“…All of these acyl-thioesters can account for non-enzymatic lysine acylation affecting protein structure and function and thereby also metabolic flux (Baldensperger and Glomb, 2021). As an example, 1,3-bisphosphoglycerate formed by glycerinaldehyd-3-phosphate dehydrogenase during glycolysis was shown to act as donor molecule for non-enzymatic lysine 3-phosphoglycerinylation resulting in impairment of their catalytic activity ultimately decreasing glycolytic flux under conditions of high glucose levels (Moellering and Cravatt, 2013;Baldensperger and Glomb, 2021). This suggests a feedback control mechanism for these enzymes via lysine ac(et)ylation.…”

Section: Metabolismmentioning

confidence: 99%

Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective

Lammers

2021

Front. Microbiol.

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Ac(et)ylation is a post-translational modification present in all domains of life. First identified in mammals in histones to regulate RNA synthesis, today it is known that is regulates fundamental cellular processes also in bacteria: transcription, translation, metabolism, cell motility. Ac(et)ylation can occur at the ε-amino group of lysine side chains or at the α-amino group of a protein. Furthermore small molecules such as polyamines and antibiotics can be acetylated and deacetylated enzymatically at amino groups. While much research focused on N-(ε)-ac(et)ylation of lysine side chains, much less is known about the occurrence, the regulation and the physiological roles on N-(α)-ac(et)ylation of protein amino termini in bacteria. Lysine ac(et)ylation was shown to affect protein function by various mechanisms ranging from quenching of the positive charge, increasing the lysine side chains’ size affecting the protein surface complementarity, increasing the hydrophobicity and by interfering with other post-translational modifications. While N-(ε)-lysine ac(et)ylation was shown to be reversible, dynamically regulated by lysine acetyltransferases and lysine deacetylases, for N-(α)-ac(et)ylation only N-terminal acetyltransferases were identified and so far no deacetylases were discovered neither in bacteria nor in mammals. To this end, N-terminal ac(et)ylation is regarded as being irreversible. Besides enzymatic ac(et)ylation, recent data showed that ac(et)ylation of lysine side chains and of the proteins N-termini can also occur non-enzymatically by the high-energy molecules acetyl-coenzyme A and acetyl-phosphate. Acetyl-phosphate is supposed to be the key molecule that drives non-enzymatic ac(et)ylation in bacteria. Non-enzymatic ac(et)ylation can occur site-specifically with both, the protein primary sequence and the three dimensional structure affecting its efficiency. Ac(et)ylation is tightly controlled by the cellular metabolic state as acetyltransferases use ac(et)yl-CoA as donor molecule for the ac(et)ylation and sirtuin deacetylases use NAD+ as co-substrate for the deac(et)ylation. Moreover, the accumulation of ac(et)yl-CoA and acetyl-phosphate is dependent on the cellular metabolic state. This constitutes a feedback control mechanism as activities of many metabolic enzymes were shown to be regulated by lysine ac(et)ylation. Our knowledge on lysine ac(et)ylation significantly increased in the last decade predominantly due to the huge methodological advances that were made in fields such as mass-spectrometry, structural biology and synthetic biology. This also includes the identification of additional acylations occurring on lysine side chains with supposedly different regulatory potential. This review highlights recent advances in the research field. Our knowledge on enzymatic regulation of lysine ac(et)ylation will be summarized with a special focus on structural and mechanistic characterization of the enzymes, the mechanisms underlying non-enzymatic/chemical ac(et)ylation are explained, recent technological progress in the field are presented and selected examples highlighting the important physiological roles of lysine ac(et)ylation are summarized.

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Pathways of Non-enzymatic Lysine Acylation

Cited by 26 publications

References 99 publications

Analysis of Glyoxal- and Methylglyoxal-Derived Advanced Glycation End Products during Grilling of Porcine Meat

Analysis of Glyoxal- and Methylglyoxal-Derived Advanced Glycation End Products during Grilling of Porcine Meat

Dynamic acylome reveals metabolite driven modifications in Syntrophomonas wolfei

Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective

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