Acetylation of proximal cysteine-lysine pairs by alcohol metabolism
Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. These factors alter proteomic and epigenetic marks, including alcohol-induced protein acetylation, which is a key post-translational modification (PTM) that regulates hepatic...
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Elsevier
2025-02-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724004403 |
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| author | Courtney D. McGinnis Peter S. Harris Brenton I.M. Graham John O. Marentette Cole R. Michel Laura M. Saba Richard Reisdorph James R. Roede Kristofer S. Fritz |
| author_facet | Courtney D. McGinnis Peter S. Harris Brenton I.M. Graham John O. Marentette Cole R. Michel Laura M. Saba Richard Reisdorph James R. Roede Kristofer S. Fritz |
| author_sort | Courtney D. McGinnis |
| collection | DOAJ |
| description | Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. These factors alter proteomic and epigenetic marks, including alcohol-induced protein acetylation, which is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ∼15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair. Here, acetylation can occur through the transfer of an acetyl moiety via an S → N transfer reaction. Alcohol-mediated redox stress is known to occur coincidentally with lysine acetylation, yet the biochemical mechanisms related to cysteine and lysine crosstalk within ALD remain unexplored. A murine model of ALD was employed to quantify hepatic cysteine redox changes and lysine acetylation, revealing that alcohol metabolism significantly reduced the cysteine thiol proteome and increased protein acetylation. Interrogating both cysteine redox and lysine acetylation datasets, 1280 protein structures generated by AlphaFold2 represented by a 3D spatial matrix were used to quantify the distances between 557,815 cysteine and lysine residues. Our analysis revealed that alcohol metabolism induces redox changes and acetylation selectively on proximal Cys-Lys pairs with an odds ratio of 1.88 (p < 0.0001). Key Cys-Lys redox signaling hubs were impacted in metabolic pathways associated with ALD, including lipid metabolism and the electron transport chain. Proximal Cys-Lys pairs exist as sets with four major motifs represented by the number of Cys and Lys residues that are pairing (Cys1:Lys1, Cysx:Lys1, Cys1:Lysx and Cysx:Lysx) each with a unique microenvironment. The motifs are composed of functionally relevant Cys-Ly altered within ALD, identifying potential therapeutic targets. Furthermore, these unique Cys-Lys redox signatures are translationally relevant as revealed by orthologous comparison with severe alcohol-associated hepatitis (SAH) explants, revealing numerous pathogenic thiol redox signals in these patients. |
| format | Article |
| id | doaj-art-8306ebacacb0474990b19b804129c09a |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-8306ebacacb0474990b19b804129c09a2025-01-14T04:12:09ZengElsevierRedox Biology2213-23172025-02-0179103462Acetylation of proximal cysteine-lysine pairs by alcohol metabolismCourtney D. McGinnis0Peter S. Harris1Brenton I.M. Graham2John O. Marentette3Cole R. Michel4Laura M. Saba5Richard Reisdorph6James R. Roede7Kristofer S. Fritz8Graduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAGraduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAGraduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAGraduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAGraduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAGraduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAGraduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAGraduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USACorresponding author. 12850 E. Montview Blvd, Campus Box C-238, Aurora, CO, 80045, USA.; Graduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USAAlcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. These factors alter proteomic and epigenetic marks, including alcohol-induced protein acetylation, which is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ∼15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair. Here, acetylation can occur through the transfer of an acetyl moiety via an S → N transfer reaction. Alcohol-mediated redox stress is known to occur coincidentally with lysine acetylation, yet the biochemical mechanisms related to cysteine and lysine crosstalk within ALD remain unexplored. A murine model of ALD was employed to quantify hepatic cysteine redox changes and lysine acetylation, revealing that alcohol metabolism significantly reduced the cysteine thiol proteome and increased protein acetylation. Interrogating both cysteine redox and lysine acetylation datasets, 1280 protein structures generated by AlphaFold2 represented by a 3D spatial matrix were used to quantify the distances between 557,815 cysteine and lysine residues. Our analysis revealed that alcohol metabolism induces redox changes and acetylation selectively on proximal Cys-Lys pairs with an odds ratio of 1.88 (p < 0.0001). Key Cys-Lys redox signaling hubs were impacted in metabolic pathways associated with ALD, including lipid metabolism and the electron transport chain. Proximal Cys-Lys pairs exist as sets with four major motifs represented by the number of Cys and Lys residues that are pairing (Cys1:Lys1, Cysx:Lys1, Cys1:Lysx and Cysx:Lysx) each with a unique microenvironment. The motifs are composed of functionally relevant Cys-Ly altered within ALD, identifying potential therapeutic targets. Furthermore, these unique Cys-Lys redox signatures are translationally relevant as revealed by orthologous comparison with severe alcohol-associated hepatitis (SAH) explants, revealing numerous pathogenic thiol redox signals in these patients.http://www.sciencedirect.com/science/article/pii/S2213231724004403Cysteine proteomicsRedoxAcetylationProtein modelingAlcohol-associated liver diseaseMass spectrometry |
| spellingShingle | Courtney D. McGinnis Peter S. Harris Brenton I.M. Graham John O. Marentette Cole R. Michel Laura M. Saba Richard Reisdorph James R. Roede Kristofer S. Fritz Acetylation of proximal cysteine-lysine pairs by alcohol metabolism Redox Biology Cysteine proteomics Redox Acetylation Protein modeling Alcohol-associated liver disease Mass spectrometry |
| title | Acetylation of proximal cysteine-lysine pairs by alcohol metabolism |
| title_full | Acetylation of proximal cysteine-lysine pairs by alcohol metabolism |
| title_fullStr | Acetylation of proximal cysteine-lysine pairs by alcohol metabolism |
| title_full_unstemmed | Acetylation of proximal cysteine-lysine pairs by alcohol metabolism |
| title_short | Acetylation of proximal cysteine-lysine pairs by alcohol metabolism |
| title_sort | acetylation of proximal cysteine lysine pairs by alcohol metabolism |
| topic | Cysteine proteomics Redox Acetylation Protein modeling Alcohol-associated liver disease Mass spectrometry |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724004403 |
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