1.8.98.2: sulfiredoxin
This is an abbreviated version!
For detailed information about sulfiredoxin, go to the full flat file.
Word Map on EC 1.8.98.2
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1.8.98.2
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peroxiredoxins
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hyperoxidation
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thioredoxins
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overoxidized
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sulfenic
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peroxidatic
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txnrd1
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sulfinylated
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deglutathionylation
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prxiii
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prdxs
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cys-so2h
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medicine
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drug development
- 1.8.98.2
- peroxiredoxins
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hyperoxidation
- thioredoxins
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overoxidized
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sulfenic
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peroxidatic
- txnrd1
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sulfinylated
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deglutathionylation
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prxiii
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prdxs
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cys-so2h
- medicine
- drug development
Reaction
Synonyms
AtSrx, cysteine-sulfinic acid reductase, neoplastic progression 3, peroxiredoxin-(S-hydroxy-S-oxocysteine) reductase, protein cysteine sulfinic acid reductase, Srx, Srx1, Srxn1, sulfiredoxin, sulfiredoxin 1, sulfiredoxin-1, sulphiredoxin
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General Information on EC 1.8.98.2 - sulfiredoxin
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GENERAL INFORMATION 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
evolution
AtSrx has more positive charges than human enzyme HsSrx. The theoretical pI of AtSrx is 9.86, much higher than 5.47 of HsSrx. There are 10 arginine residues and 7 lysine residues in AtSrx but only 5 arginine residues and 3 lysine residues in HsSrx. For negatively charged amino acids residues, there are 6 glutamic acid residues and 4 aspartic acid residues in AtSrx, while there are 2 glutamic acid residues and 8 aspartic acid residues in HsSrx. Abundant charged amino acids of AtSrx provide more positive charge at ADP binding pocket and more interaction with active
malfunction
physiological function
additional information
malfunction
inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death
malfunction
loss of the extended active site interface within engineered peroxiredoxin isozymes, Prx2 and Prx3, dimers yields variants more resistant to hyperoxidation and repair by enzyme Srx
malfunction
Srx knockdown sensitizes lung cancer cells to endoplasmic reticulum (ER) stress-induced cell death. Inhibition of Srx results in oxidative stress-induced mitochondrial damage and caspase activation, leading to the apoptosis of lung adenocarcinoma cells. Mutation of Cys99 to Ala (C99A) leads to a complete loss of both enzymatic activity and binding to substrates such as Prxs
physiological function
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the antioxidant function of 2-Cys peroxiredoxin, Prx, EC 1.11.1.15, involves the oxidation of its conserved peroxidatic cysteine to sulfinic acid that is recycled by a reductor agent. Sulfiredoxin reduces the sulfinic 2-Cys Prx, Prx-SO2H. The activity of sulfiredoxin is dependent on the concentration of the sulfinic form of Prx and the conserved Srx is capable of regenerating the functionality of both pea and Arabidopsis Prx-SO2H
physiological function
exposure of low steady-state levels ofH2O2 to A-549 or wild-type mouse embryonic fibroblast cells does not lead to any significant change in oxidative injury. Loss-of-function studies using sulfiredoxin-depleted A549 and sulfiredoxin -/- cells demonstrate a dramatic increase in extra- and intracellular H2O2, sulfinic 2-Cys peroxiredoxins, and apoptosis. Concomitant with hyperoxidation of mitochondrial peroxiredoxin Prx III, sulfiredoxin-depleted cells show an activation of mitochondria-mediated apoptotic pathways including mitochondria membrane potential collapse, cytochrome c release, and caspase activation
physiological function
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sulfiredoxin Srx1 reactivates the yeast peroxiredoxin Prx1 peroxidase activity that is inactivated by H2O2, whereas it decreases the chaperone activity enhanced by H2O2. Srx1 dissociates the H2O2-induced high molecular weight Prx1 complex, and the Srx1 Cys84 residue is critical for its dissociation
physiological function
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enzyme induction is the pivotal compensatory protection mechanism against oxidative stress in diabetes or hyperglycaemia
physiological function
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mitochondrial H2O2 signaling is controlled by the concerted action of peroxiredoxin III and sulfiredoxin
physiological function
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sulfiredoxin-1 protects PC-12 cells against oxidative stress induced by hydrogen peroxide
physiological function
2-Cys peroxiredoxins (Prxs) are highly abundant peroxidases that play as peroxide sensors promoting H2O2 signaling and oxidative stress resistance in respond to elevated oxidative levels. Prxs use a peroxidatic cysteine (Cys-SpH) to catalytically decompose peroxides. During normal catalysis, the peroxidatic Cys residue (Cys-SpH) is oxidized to Cys sulfenic acid (Cys-SpOH) and further inactivation by peroxidation of the peroxidatic cysteine residue to Cys sulfinic acid (Cys-SpO2-). Importantly, Prxs can be reactivated with the Cys-SPO2- moiety reduced to Cys sulfenic acid (Cys-SpOH) by a repaired enzyme known as sulfiredoxin (Srx). This reversible event is a physiologically important process against the oxidative stress that can allow cells to return to homeostasis
physiological function
Prxs, a type of the antioxidant peroxidases in cells, are including thioredoxin- and sulfiredoxin-dependent peroxidases, which play a crucial role in decreasing ROS levels in cells by taking part in the catalytic cycle. During the catalytic cycle for the reduction of Prx, a Cys active site residue (Cys-SH) of Prx is oxidized to a cysteine sulfenic acid (Cys-SOH) after forming a disulfide bond with the other cysteine of the adjacent Prx monomer. The oxidized Prx is reduced back to the initial form by thioredoxin (Trx). Moreover, the oxidized cysteine of Prx (Cys-SOH) can be oxidized again into sulfinic acid (Cys-SO2H). Srx exclusively reduces sulfinic acid to sulfenic acid by an ATP-dependent reaction catalyzed in presence of Mg2+. Antioxidant peroxidases, including Prx and Srx, are abundantly expressed in various cancers cells, and cancer cells are known to be more vulnerable to the toxicity of ROS under oxidative stress conditions than normal cells
physiological function
Sulfiredoxin (Srx) reduces hyperoxidized 2-cysteine-containing peroxiredoxins (Prxs) and protects cells against oxidative stress. Cellular peroxidases, including Prxs, are antioxidant enzymes that contribute to the development of lung cancer. Srx is highly expressed in primary specimens of lung cancer patients and plays a pivotal role in lung tumorigenesis and cancer progression. Srx has an oncogenic function that promotes the invasion and metastasis of lung cancer cells. In response to ER stress but not to oxidative stress, Srx exhibits an increased association with the endoplasmic reticulum (ER)-resident protein thioredoxin domain-containing protein 5 (TXNDC5), facilitating the retention of Srx in the ER. The overall amounts of TXNDC5 associated with Srx are not affected by the exposure of cells to exogenous H2O2 as high as 1 mM, functional significance of Srx and TXNDC5 at different stages of lung cancer. Of note, TXNDC5 knockdown in lung cancer cells inhibits cell proliferation and represses anchorage-independent colony formation and migration, but increases cell invasion and activation of mitogen-activated protein kinases. Expression of TXNDC5 stimulates anchorage-independent colony formation but inhibits cell invasion. Knockdown of TXNDC5 enhances EGF-induced MAPK activation. TXNDC5 is highly expressed in patient-derived lung cancer specimen. Patients with high Srx levels have significantly shorter survival and those with high TXNDC5 levels have longer survival. The function of Srx appears to be necessary to maintain the redox balance in cancer cells
physiological function
the repair and reactivation of the hyperoxidized Prxs by Srx is an important cellular process, hydrogen sulfide repair of hyperoxidized 2-Cys Prxs by human sulfiredoxin (Srx), structural requirements, peroxiredoxin catalytic and sulfiredoxin repair cycles, detailed overview. The physiological reductants hydrogen sulfide (H2S) and glutathione (GSH) show relative efficacy in this reaction. Prx isoform-dependent use of and potential cooperation between GSH and H2S in supporting Srx activity
physiological function
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the antioxidant function of 2-Cys peroxiredoxin, Prx, EC 1.11.1.15, involves the oxidation of its conserved peroxidatic cysteine to sulfinic acid that is recycled by a reductor agent. Sulfiredoxin reduces the sulfinic 2-Cys Prx, Prx-SO2H. The activity of sulfiredoxin is dependent on the concentration of the sulfinic form of Prx and the conserved Srx is capable of regenerating the functionality of both pea and Arabidopsis Prx-SO2H
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additional information
Cys99 of Srx is critical for its catalytic activity
additional information
the crystal structure of sulfiredoxin from Arabidopsis thaliana (AtSrx) displays a typical ParB/Srx fold with an ATP bound at a conservative nucleotide binding motif GCHR. Both the ADP binding pocket and the putative AtSrx-AtPrxA interaction surface of AtSrx are more positively charged comparing to HsSrx, suggesting a robust mechanism of AtSrx. Complex formation analysis of enzyme AtSrx with wild-type and F149Q/C241S mutant AtPrxA substrates
additional information
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the crystal structure of sulfiredoxin from Arabidopsis thaliana (AtSrx) displays a typical ParB/Srx fold with an ATP bound at a conservative nucleotide binding motif GCHR. Both the ADP binding pocket and the putative AtSrx-AtPrxA interaction surface of AtSrx are more positively charged comparing to HsSrx, suggesting a robust mechanism of AtSrx. Complex formation analysis of enzyme AtSrx with wild-type and F149Q/C241S mutant AtPrxA substrates
additional information
the decameric Srx-Prx1 complex reveals extended binding interface, human Prx1 and Prx2 form a decameric toroid. The crystal structure of the toroidal Prx1-Srx complex shows an extended active site interface. Structural basis for the ability of Srx to reduce the hyperoxidized form of human Prxs, juxtaposition of the two active-site interfaces of the two proteins and wrapping of the Prx C-terminus around Srx in an essential interaction, overview
additional information
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the decameric Srx-Prx1 complex reveals extended binding interface, human Prx1 and Prx2 form a decameric toroid. The crystal structure of the toroidal Prx1-Srx complex shows an extended active site interface. Structural basis for the ability of Srx to reduce the hyperoxidized form of human Prxs, juxtaposition of the two active-site interfaces of the two proteins and wrapping of the Prx C-terminus around Srx in an essential interaction, overview
