Catalytic mechanism of thioltransferase

Yang, Yanfeng; Wells, William W.

doi:10.1016/s0021-9258(18)98965-9

Cited by 44 publications

(20 citation statements)

References 14 publications

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“…3B). The NH 2 -terminal active site cysteine of the active site motif (Cys 23 of human GLRX) is required for both disulfide bond reduction and deglutathionylation (67,68,270,271). This cysteine differs from the COOH-terminal active site cysteine (Cys 26 ) in that Cys 23 is exposed to the exterior of the protein and is solvent accessible, whereas Cys 26 is buried and is inaccessible to solvent (117,266).…”

Section: Discovery and Biochemistry Of Glutaredoxinsmentioning

confidence: 99%

“…In E. coli GLRX, the COOH-terminal active site cysteine contributes to the deglutathionylation reaction, as cysteine-to-serine mutation significantly reduces deglutathionylation activity (28,215). In contrast, mammalian GLRX requires only the active site NH 2terminal cysteine for the deglutathionylation, as the mutation of individual or all four cysteines other than active site Cys 23 does not change the deglutathionylating activity (117,268,270,271). Mutation of the COOH-terminal active site cysteine to serine (Cys 26 Ser in human GLRX) actually increases the enzymatic activity of GLRX (268,271).…”

Section: Discovery and Biochemistry Of Glutaredoxinsmentioning

confidence: 99%

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Dysregulation of the glutaredoxin/S-glutathionylation redox axis in lung diseases

Chia

Elko

Aboushousha

et al. 2020

American Journal of Physiology-Cell Physiology

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Glutathione is a major redox buffer, reaching millimolar concentrations within cells and high micromolar concentrations in airways. While glutathione has been traditionally known as an antioxidant defense mechanism that protects the lung tissue from oxidative stress, glutathione more recently has become recognized for its ability to become covalently conjugated to reactive cysteines within proteins, a modification known as S-glutathionylation (or S-glutathiolation or protein mixed disulfide). S-glutathionylation has the potential to change the structure and function of the target protein, owing to its size (the addition of three amino acids) and charge (glutamic acid). S-glutathionylation also protects proteins from irreversible oxidation, allowing them to be enzymatically regenerated. Numerous enzymes have been identified to catalyze the glutathionylation/deglutathionylation reactions, including glutathione S-transferases and glutaredoxins. Although protein S-glutathionylation has been implicated in numerous biological processes, S-glutathionylated proteomes have largely remained unknown. In this paper, we focus on the pathways that regulate GSH homeostasis, S-glutathionylated proteins, and glutaredoxins, and we review methods required toward identification of glutathionylated proteomes. Finally, we present the latest findings on the role of glutathionylation/glutaredoxins in various lung diseases: idiopathic pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease.

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Section: Discovery and Biochemistry Of Glutaredoxinsmentioning

confidence: 99%

Section: Discovery and Biochemistry Of Glutaredoxinsmentioning

confidence: 99%

Dysregulation of the glutaredoxin/S-glutathionylation redox axis in lung diseases

Chia

Elko

Aboushousha

et al. 2020

American Journal of Physiology-Cell Physiology

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“…To reduce protein disulfide bridges or glutathione-mixed disulfides, glutaredoxins either employ the monothiol or the dithiol mechanism. Dithiol and monothiol mechanism are distinguished by the number of cysteines used for catalysis (Figure I4A and B) [1,9,74,79,93,94,[101][102][103]. The reaction sequence of both mechanisms starts with the oxidative half reaction, during which the substrate becomes reduced and the glutaredoxin oxidized.…”

Section: Glutathione Binding and Reaction Mechanisms Of Glutaredoxinsmentioning

confidence: 99%

“…Glutathione is not used as an electron donor during this step (Figure I4B, step E). The resulting intramolecular disulfide bridge of the glutaredoxin is subsequently reduced by two molecules of glutathione (Figure I4B, steps G, C, and D) or by TR or FTR (Figure I4B, step H) [1,9,74,78,79,93,94,[101][102][103][104][105][106].…”

Section: Glutathione Binding and Reaction Mechanisms Of Glutaredoxinsmentioning

confidence: 99%

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Functional analysis of the Arabidopsis thaliana glutaredoxin ROXY9

Treffon¹

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The solution structure solved by nuclear magnetic resonance (NMR) spectroscopy of the poplar CPYC-type glutaredoxin GRXC1 (CGYC acitve site) was determined by Feng et al. (2006) (PDB accession: 1Z7P [81]). The PDB data file was used to prepare the picture of the ribbon structure in PyMOL. The first and the last active site cysteine (CysA and CysB, respectively) are shown as yellow stick representations. A red coloring marks the sites of residues important for glutathione binding [1,79]. The figure was in parts taken from Lillig et al. (2008) and Gutsche et al. (2015) and modified [79,80].Higher plants contain four cytosolic CPYC glutaredoxins: GRXC1, GRXC2, GRXC3 and GRXC4, and at least one chloroplastic CPYC glutaredoxin named GRXS12. In Brassicacea, an additional CPYC glutaredoxin, GRXC5, is located in the chloroplast [77,94,96,113,137]. GRXC1 and GRXC2 differ in their properties slightly from GRXC3 and GRXC4, forming two subclasses of CPYC glutaredoxins. While GRXC1 and GRXC2 might dimerize via a disulfide bridge, the other glutaredoxins do not. This might result in different reaction mechanisms [77]. GRXC1 and GRXC2 have been studied extensively at the biochemical level and by mutant analysis. They are indispensable for plant Still, the ALWL motif is not conserved in all CC-type glutaredoxins found in A. thaliana. ROXY6, 7, 8, 9 and 20 lack this motif, and are not able to repress TGA2 and PAN. Interestingly, ROXY9 and ROXY8 were shown to repress the activity of TGA1 and TGA4 [145,[155][156][157]168,170]. In this context, Willmer (2014) could show that several CC-type glutaredoxins from A. thaliana are able to interact with so-called TIFY proteins [178]. TIFY-proteins are has a different function within the plant. Clade II TGA factors were extensively studied with respect to their function in the plant defense response "systemic acquired resistance". To regulate the defense program against biotrophic pathogens, clade II TGA factors interact with the SA-binding transcriptional regulators NPR1, NPR3 and NPR4 [192,193,[196][197][198][199][200][201]. NPR1 and TGA2 were found to bind constitutively to the promoter of the defense gene PR-1. However, under non-inducing conditions, TGA2 is bound in high-order complexes to the DNA. These complexes are formed via its N-terminal domain and do not interact with NPR1, thereby preventing PR-1 transcription Beside their function in response to biotic stress [157,159,221], TGA1 and TGA4 also regulate hyponastic growth [155,156], a response towards low light conditions, flooding or heat. Normally, the rosette leaves of A. thaliana are spread flat on the soil. Since in this state, A. thaliana is sensitive to the aforementioned environmental stresses, it raises its leaves in order to reach This peptide hormone induces the transcription of ROXY9 and its paralogue ROXY6 in the leaves. Both, ROXY9 and ROXY6, are transported via the phloem to the roots in those regions of the soil rich in nitrogen. This serves to activate NRT2. 1 [154]. This activation of NRT2.1 is, however, in cont...

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