Cysteine Oxidation by the Superoxide Radical: A Theoretical Study

Cardey, Bruno; Enescu, Mironel

doi:10.1002/cphc.200900010

Cited by 19 publications

(6 citation statements)

References 23 publications

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“…Overall, our mass spectrometric studies confirm that DA and its derivatives are capable of oxidizing Aβ (especially, at M35) with and/or without Cu(II) under aerobic conditions via their oxidative transformation, which could be the source of their observed antiamyloidogenic activity. Note that (i) our results did not exhibit the formation of transformed DQ−protein adducts, as proposed in the previous studies (structure of DQ is shown in Figure 1b); 2,15,51 (ii) histidine residues (i.e., H13 and H14), 45,49,51 along with M35, could not be ruled out as oxidation sites.…”

Section: •−supporting

confidence: 69%

Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-β Aggregation, Oxidative Stress, and Inflammation in Alzheimer’s Disease

Nam

Derrick

Lee

et al. 2018

ACS Chem. Neurosci.

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A catecholamine neurotransmitter, dopamine (DA), is suggested to be linked to the pathology of dementia; however, the involvement of DA and its structural analogues in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that DA and its rationally designed structural derivatives (1-6) based on DA's oxidative transformation are able to modulate multiple pathological elements found in AD [i.e., metal ions, metal-free amyloid-β (Aβ), metal-bound Aβ (metal-Aβ), and reactive oxygen species (ROS)], with demonstration of detailed molecular-level mechanisms. Our multidisciplinary studies validate that the protective effects of DA and its derivatives on Aβ aggregation and Aβ-mediated toxicity are induced by their oxidative transformation with concomitant ROS generation under aerobic conditions. In particular, DA and the derivatives (i.e., 3 and 4) show their noticeable anti-amyloidogenic ability toward metal-free Aβ and/or metal-Aβ, verified to occur via their oxidative transformation that facilitates Aβ oxidation. Moreover, in primary pan-microglial marker (CD11b)-positive cells, the major producers of inflammatory mediators in the brain, DA and its derivatives significantly diminish inflammation and oxidative stress triggered by lipopolysaccharides and Aβ through the reduced induction of inflammatory mediators as well as upregulated expression of heme oxygenase-1, the enzyme responsible for production of antioxidants. Collectively, we illuminate how DA and its derivatives could prevent multiple pathological features found in AD. The overall studies could advance our understanding regarding distinct roles of neurotransmitters in AD and identify key interactions for alleviation of AD pathology.

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Section: •−supporting

confidence: 69%

Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-β Aggregation, Oxidative Stress, and Inflammation in Alzheimer’s Disease

Nam

Derrick

Lee

et al. 2018

ACS Chem. Neurosci.

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“…This also indicated that although cysteine redox-sensitivity is mainly affected by protein structural environment as revealed by some previous studies [39–41], redox-sensitive cysteines can still be inferred using only sequence features with moderate accuracy. Sequence-based prediction is much more advantageous in that it is not limited by structure data thus can be widely used for prediction as long as the protein sequence data is available.…”

Section: Resultssupporting

confidence: 65%

Prediction of redox-sensitive cysteines using sequential distance and other sequence-based features

et al. 2016

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BackgroundReactive oxygen species can modify the structure and function of proteins and may also act as important signaling molecules in various cellular processes. Cysteine thiol groups of proteins are particularly susceptible to oxidation. Meanwhile, their reversible oxidation is of critical roles for redox regulation and signaling. Recently, several computational tools have been developed for predicting redox-sensitive cysteines; however, those methods either only focus on catalytic redox-sensitive cysteines in thiol oxidoreductases, or heavily depend on protein structural data, thus cannot be widely used.ResultsIn this study, we analyzed various sequence-based features potentially related to cysteine redox-sensitivity, and identified three types of features for efficient computational prediction of redox-sensitive cysteines. These features are: sequential distance to the nearby cysteines, PSSM profile and predicted secondary structure of flanking residues. After further feature selection using SVM-RFE, we developed Redox-Sensitive Cysteine Predictor (RSCP), a SVM based classifier for redox-sensitive cysteine prediction using primary sequence only. Using 10-fold cross-validation on RSC758 dataset, the accuracy, sensitivity, specificity, MCC and AUC were estimated as 0.679, 0.602, 0.756, 0.362 and 0.727, respectively. When evaluated using 10-fold cross-validation with BALOSCTdb dataset which has structure information, the model achieved performance comparable to current structure-based method. Further validation using an independent dataset indicates it is robust and of relatively better accuracy for predicting redox-sensitive cysteines from non-enzyme proteins.ConclusionsIn this study, we developed a sequence-based classifier for predicting redox-sensitive cysteines. The major advantage of this method is that it does not rely on protein structure data, which ensures more extensive application compared to other current implementations. Accurate prediction of redox-sensitive cysteines not only enhances our understanding about the redox sensitivity of cysteine, it may also complement the proteomics approach and facilitate further experimental investigation of important redox-sensitive cysteines.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1185-4) contains supplementary material, which is available to authorized users.

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“…In addition, it has been reported that cysteine can be modified by superoxide (10). Therefore, we hypothesized that ASA-induced increases in superoxide production might modify the cysteine residue of the ZO-1 protein.…”

Section: Discussionmentioning

confidence: 95%

Acetyl salicylic acid induces damage to intestinal epithelial cells by oxidation-related modifications of ZO-1

Fukui

Naito

Handa

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Acetyl salicylic acid (ASA) is one of the most frequently prescribed medications for the secondary prevention of cardiovascular and cerebrovascular events. It has recently been reported to cause small intestinal mucosal injury at a considerably higher rate than previously believed. The aim of this study is to investigate the mechanism by which this occurs using an in vitro small intestine model focusing on the role of oxidative stress and cell permeability. Differentiated Caco-2 exhibits a phenotype similar to human small intestinal epithelium. We measured whether ASA induced the increase of differentiated Caco-2 permeability, the decrease of tight junction protein expression, the production of reactive oxygen species (ROS), and the expression of ROS-modified zonula occludens-1 (ZO-1) protein. In some experiments, Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, a superoxide dismutase mimetic) was used. The nontoxic concentration of ASA decreased transepithelial electrical resistance and increased the flux of fluorescein isothiocyanate-conjugated dextran across Caco-2 in a time-dependent manner. The same concentration of ASA significantly decreased ZO-1 expression among TJ proteins as assessed by Western blot and immunocytochemistry and increased ROS production and the expression of oxidative stress-modified ZO-1 protein. However, MnTMPyP suppressed the ASA-induced increased intercellular permeability and the ASA-induced ROS-modified ZO-1 expression. Our findings indicate that ASA-induced ROS production can specifically modify the expression of ZO-1 protein and induce increased cell permeability, which may ultimately cause small intestinal mucosal injury.

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Cysteine Oxidation by the Superoxide Radical: A Theoretical Study

Cited by 19 publications

References 23 publications

Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-β Aggregation, Oxidative Stress, and Inflammation in Alzheimer’s Disease

Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-β Aggregation, Oxidative Stress, and Inflammation in Alzheimer’s Disease

Prediction of redox-sensitive cysteines using sequential distance and other sequence-based features

Acetyl salicylic acid induces damage to intestinal epithelial cells by oxidation-related modifications of ZO-1

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