Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families
Cysteine residues have a rich chemistry and play a critical role in the catalytic activity of a plethora of enzymes. However, cysteines are susceptible to oxidation by Reactive Oxygen and Nitrogen Species, leading to a loss of their catalytic function. Therefore, cysteine oxidation is emerging as a...
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Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_1553734X_v11_n3_p_Defelipe http://hdl.handle.net/20.500.12110/paper_1553734X_v11_n3_p_Defelipe |
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paper:paper_1553734X_v11_n3_p_Defelipe2023-06-08T16:23:07Z Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families acid amide carbon nitrogen hydrolase cysteine DJ 1 protein glutamine amidotransferase hydrolase phosphatase protein tyrosine phosphatase SNO glutamine amidotransferase sulfenic acid sulfenyl amide thiosulfate sulfurtransferase transferase unclassified drug amide cysteine protein sulfenic acid derivative amino acid analysis Article catalysis chemical analysis chemical structure conformational transition controlled study molecular dynamics molecular evolution oxidation reduction reaction protein folding protein function protein localization reaction time residue analysis sequence analysis biology chemistry metabolism molecular model oxidation reduction reaction protein conformation Amides Computational Biology Cysteine Models, Molecular Oxidation-Reduction Protein Conformation Proteins Sulfenic Acids Cysteine residues have a rich chemistry and play a critical role in the catalytic activity of a plethora of enzymes. However, cysteines are susceptible to oxidation by Reactive Oxygen and Nitrogen Species, leading to a loss of their catalytic function. Therefore, cysteine oxidation is emerging as a relevant physiological regulatory mechanism. Formation of a cyclic sulfenyl amide residue at the active site of redox-regulated proteins has been proposed as a protection mechanism against irreversible oxidation as the sulfenyl amide intermediate has been identified in several proteins. However, how and why only some specific cysteine residues in particular proteins react to form this intermediate is still unknown. In the present work using in-silico based tools, we have identified a constrained conformation that accelerates sulfenyl amide formation. By means of combined MD and QM/MM calculation we show that this conformation positions the NH backbone towards the sulfenic acid and promotes the reaction to yield the sulfenyl amide intermediate, in one step with the concomitant release of a water molecule. Moreover, in a large subset of the proteins we found a conserved beta sheet-loop-helix motif, which is present across different protein folds, that is key for sulfenyl amide production as it promotes the previous formation of sulfenic acid. For catalytic activity, in several cases, proteins need the Cysteine to be in the cysteinate form, i.e. a low pK<inf>a</inf> Cys. We found that the conserved motif stabilizes the cysteinate by hydrogen bonding to several NH backbone moieties. As cysteinate is also more reactive toward ROS we propose that the sheet-loop-helix motif and the constraint conformation have been selected by evolution for proteins that need a reactive Cys protected from irreversible oxidation. Our results also highlight how fold conservation can be correlated to redox chemistry regulation of protein function. © 2015 Defelipe et al. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_1553734X_v11_n3_p_Defelipe http://hdl.handle.net/20.500.12110/paper_1553734X_v11_n3_p_Defelipe |
institution |
Universidad de Buenos Aires |
institution_str |
I-28 |
repository_str |
R-134 |
collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
topic |
acid amide carbon nitrogen hydrolase cysteine DJ 1 protein glutamine amidotransferase hydrolase phosphatase protein tyrosine phosphatase SNO glutamine amidotransferase sulfenic acid sulfenyl amide thiosulfate sulfurtransferase transferase unclassified drug amide cysteine protein sulfenic acid derivative amino acid analysis Article catalysis chemical analysis chemical structure conformational transition controlled study molecular dynamics molecular evolution oxidation reduction reaction protein folding protein function protein localization reaction time residue analysis sequence analysis biology chemistry metabolism molecular model oxidation reduction reaction protein conformation Amides Computational Biology Cysteine Models, Molecular Oxidation-Reduction Protein Conformation Proteins Sulfenic Acids |
spellingShingle |
acid amide carbon nitrogen hydrolase cysteine DJ 1 protein glutamine amidotransferase hydrolase phosphatase protein tyrosine phosphatase SNO glutamine amidotransferase sulfenic acid sulfenyl amide thiosulfate sulfurtransferase transferase unclassified drug amide cysteine protein sulfenic acid derivative amino acid analysis Article catalysis chemical analysis chemical structure conformational transition controlled study molecular dynamics molecular evolution oxidation reduction reaction protein folding protein function protein localization reaction time residue analysis sequence analysis biology chemistry metabolism molecular model oxidation reduction reaction protein conformation Amides Computational Biology Cysteine Models, Molecular Oxidation-Reduction Protein Conformation Proteins Sulfenic Acids Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families |
topic_facet |
acid amide carbon nitrogen hydrolase cysteine DJ 1 protein glutamine amidotransferase hydrolase phosphatase protein tyrosine phosphatase SNO glutamine amidotransferase sulfenic acid sulfenyl amide thiosulfate sulfurtransferase transferase unclassified drug amide cysteine protein sulfenic acid derivative amino acid analysis Article catalysis chemical analysis chemical structure conformational transition controlled study molecular dynamics molecular evolution oxidation reduction reaction protein folding protein function protein localization reaction time residue analysis sequence analysis biology chemistry metabolism molecular model oxidation reduction reaction protein conformation Amides Computational Biology Cysteine Models, Molecular Oxidation-Reduction Protein Conformation Proteins Sulfenic Acids |
description |
Cysteine residues have a rich chemistry and play a critical role in the catalytic activity of a plethora of enzymes. However, cysteines are susceptible to oxidation by Reactive Oxygen and Nitrogen Species, leading to a loss of their catalytic function. Therefore, cysteine oxidation is emerging as a relevant physiological regulatory mechanism. Formation of a cyclic sulfenyl amide residue at the active site of redox-regulated proteins has been proposed as a protection mechanism against irreversible oxidation as the sulfenyl amide intermediate has been identified in several proteins. However, how and why only some specific cysteine residues in particular proteins react to form this intermediate is still unknown. In the present work using in-silico based tools, we have identified a constrained conformation that accelerates sulfenyl amide formation. By means of combined MD and QM/MM calculation we show that this conformation positions the NH backbone towards the sulfenic acid and promotes the reaction to yield the sulfenyl amide intermediate, in one step with the concomitant release of a water molecule. Moreover, in a large subset of the proteins we found a conserved beta sheet-loop-helix motif, which is present across different protein folds, that is key for sulfenyl amide production as it promotes the previous formation of sulfenic acid. For catalytic activity, in several cases, proteins need the Cysteine to be in the cysteinate form, i.e. a low pK<inf>a</inf> Cys. We found that the conserved motif stabilizes the cysteinate by hydrogen bonding to several NH backbone moieties. As cysteinate is also more reactive toward ROS we propose that the sheet-loop-helix motif and the constraint conformation have been selected by evolution for proteins that need a reactive Cys protected from irreversible oxidation. Our results also highlight how fold conservation can be correlated to redox chemistry regulation of protein function. © 2015 Defelipe et al. |
title |
Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families |
title_short |
Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families |
title_full |
Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families |
title_fullStr |
Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families |
title_full_unstemmed |
Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families |
title_sort |
protein topology determines cysteine oxidation fate: the case of sulfenyl amide formation among protein families |
publishDate |
2015 |
url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_1553734X_v11_n3_p_Defelipe http://hdl.handle.net/20.500.12110/paper_1553734X_v11_n3_p_Defelipe |
_version_ |
1768545665507393536 |