Reactive cysteine in proteins: Protein folding, antioxidant defense, redox signaling and more

Netto, Luís Eduardo Soares; Oliveira, Marcos Aurélio Farias de; Monteiro, Gisele; Demasi, Ana Paula Dias; Cussiol, José Renato Rosa; Discola, Karen Fulan; Demasi, Marilene; Silva, Gustavo Monteiro; Alves, Simone; Faria, Victor Genu; Horta, Bruno Brasil

doi:10.1016/j.cbpc.2006.07.014

Cited by 112 publications

(99 citation statements)

References 107 publications

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“…to remove H 2 O 2 was found to be approximately 12-fold higher under these conditions (Table 1), in accordance with the higher levels of antioxidant enzymes that were anticipated in the absence of repression by glucose [16].…”

Section: S Proteasome S-glutathionylation Is Determined By Yeast Cesupporting

confidence: 79%

“…Cysteinyl-redox modification is a widespread enzymatic and regulatory mechanism that is coupled to intracellular redox signaling [16,17]. Protein S-glutathionylation is among these modifications and is related to many regulatory pathways, ranging from gene expression to the modification of transcription factors to enzymatic modulation [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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20S proteasome activity is modified via S-glutathionylation based on intracellular redox status of the yeast Saccharomyces cerevisiae: Implications for the degradation of oxidized proteins

Demasi

Hand

Ohara

et al. 2014

Archives of Biochemistry and Biophysics

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Section: S Proteasome S-glutathionylation Is Determined By Yeast Cesupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

20S proteasome activity is modified via S-glutathionylation based on intracellular redox status of the yeast Saccharomyces cerevisiae: Implications for the degradation of oxidized proteins

Demasi

Hand

Ohara

et al. 2014

Archives of Biochemistry and Biophysics

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“…7B, the other conformation is represented in supplemental Fig. S7) (12,20). Thus, the pK a of 6.2 for the peroxidatic cysteine residue of XfPrxQ determined here (Fig.…”

Section: Resultsmentioning

confidence: 65%

“…The 2-Cys Prx group can be further divided into typical 2-Cys Prx and atypical 2-Cys Prx, according to the localization of the additional cysteine involved in catalysis (12,13). All groups share a common initial step of catalysis; the oxidation of a conserved reactive cysteine (the so-called peroxidatic cysteine) to a sulfenic acid intermediate (Cys-SOH) with the reduction of the hydroperoxide substrate to the correspondent alcohol.…”

mentioning

confidence: 99%

Structural and Biochemical Characterization of Peroxiredoxin Qβ from Xylella fastidiosa

Horta

Oliveira

Discola

et al. 2010

Journal of Biological Chemistry

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The phytopathogenic bacterium Xylella fastidiosa is the etiological agent of various plant diseases. To survive under oxidative stress imposed by the host, microorganisms express antioxidant proteins, including cysteine-based peroxidases named peroxiredoxins. This work is a comprehensive analysis of the catalysis performed by PrxQ from X. fastidiosa (XfPrxQ) that belongs to a peroxiredoxin class still poorly characterized and previously considered as moderately reactive toward hydroperoxides. Contrary to these assumptions, our competitive kinetics studies have shown that the second-order rate constants of the peroxidase reactions of XfPrxQ with hydrogen peroxide and peroxynitrite are in the order of 10 7 and 10 6 M ؊1 s ؊1 , respectively, which are as fast as the most efficient peroxidases. The XfPrxQ disulfides were only slightly reducible by dithiothreitol; therefore, the identification of a thioredoxin system as the probable biological reductant of XfPrxQ was a relevant finding. We also showed by site-specific mutagenesis and mass spectrometry that an intramolecular disulfide bond between Cys-47 and Cys-83 is generated during the catalytic cycle. Furthermore, we elucidated the crystal structure of XfPrxQ C47S in which Ser-47 and Cys-83 lie ϳ12.3 Å apart. Therefore, significant conformational changes are required for disulfide bond formation. In fact, circular dichroism data indicated that there was a significant redox-dependent unfolding of ␣-helices, which is probably triggered by the peroxidatic cysteine oxidation. Finally, we proposed a model that takes data from this work as well data as from the literature into account.

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“…Although all three BCs are conserved in both Keap1a and Keap1b, the amino acid adjacent to BC2 is a threonine in Keap1a and a lysine in Keap1b and other vertebrate Keap1 proteins. It is known that adjacent basic residues stabilize the thiolate form of the cysteine residue, thus enhancing its reactivity (2,29). Based on the fact that DEM could cancel the Nrf2 repression activity of Keap1b but not that of Keap1a, we predicted that BC2 is a sensor site for DEM and that the adjacent lysine residue in Keap1b and other Keap1 proteins is critical for its reactivity.…”

Section: Resultsmentioning

confidence: 96%

The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds

Kobayashi

Iwamoto

et al. 2009

Molecular and Cellular Biology

575

544

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Animals have evolved defense systems for surviving in a chemically diverse environment. Such systems should demonstrate plasticity, such as adaptive immunity, enabling a response to even unknown chemicals. The antioxidant transcription factor Nrf2 is activated in response to various electrophiles and induces cytoprotective enzymes that detoxify them. We report here the discovery of a multiple sensing mechanism for Nrf2 activation using zebrafish and 11 Nrf2-activating compounds. First, we showed that six of the compounds tested specifically target Cys-151 in Keap1, the ubiquitin ligase for Nrf2, while two compounds target Cys-273. Second, in addition to Nrf2 and Keap1, a third factor was deemed necessary for responding to three of the compounds. Finally, we isolated a zebrafish mutant defective in its response to seven compounds but not in response to the remaining four. These results led us to categorize Nrf2 activators into six classes and hypothesize that multiple sensing allows enhanced plasticity in the system.Nrf2 is a transcription factor that transactivates cytoprotective genes through a common DNA regulatory element, called the antioxidant response element or electrophile response element (18, 24). Nrf2 target genes are multifarious and encode phase 2 detoxifying enzymes, antioxidant proteins, enzymes for glutathione biosynthesis, ABC transporters, scavenger receptors, transcription factors, proteases, chaperone proteins, and so forth (23). Under basal conditions, Nrf2 is rapidly degraded by proteasomes, and little induction of target genes is observed. This degradation is controlled by Keap1, an Nrf2-specific adaptor protein for the Cul3 ubiquitin ligase complex (12,20). Nrf2-activating compounds block Keap1-dependent Nrf2 ubiquitination, leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes.A number of Nrf2 activators have been found but, interestingly, no common structures were identified among them (23). Talalay and coworkers classified Nrf2-activating compounds into the following 10 distinct classes based on their chemical structures (7): diphenols, Michael reaction acceptors, isothiocyanates, thiocarbamates, trivalent arsenicals, 1,2-dithiole-3-thiones, hydroperoxides, vicinal dimercaptans, heavy metals, and polyenes. A current pursuit is unraveling how cells detect these chemical compounds and transduce their signals into the activation of Nrf2. Keap1 has many highly reactive cysteine residues that have the potential to sense electrophilic Nrf2 activators by forming covalent adducts with them. We and others have therefore proposed the model that Nrf2-activating compounds directly modify the sulfhydryl groups of Keap1 cysteines by oxidation, reduction, or alkylation, which alters the conformation of Keap1 and ceases the ubiquitination of Nrf2 (7,24). In fact, mass spectrometry (MS) studies revealed that some Nrf2-activating compounds can covalently react with cysteines in mouse or human Keap1. For example, dexamethasone 21-mesylate with ; iodo...

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Reactive cysteine in proteins: Protein folding, antioxidant defense, redox signaling and more

Cited by 112 publications

References 107 publications

20S proteasome activity is modified via S-glutathionylation based on intracellular redox status of the yeast Saccharomyces cerevisiae: Implications for the degradation of oxidized proteins

20S proteasome activity is modified via S-glutathionylation based on intracellular redox status of the yeast Saccharomyces cerevisiae: Implications for the degradation of oxidized proteins

Structural and Biochemical Characterization of Peroxiredoxin Qβ from Xylella fastidiosa

The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds

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