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Information on EC 1.8.98.2 - sulfiredoxin and Organism(s) Homo sapiens and UniProt Accession Q9BYN0
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1.8.98.2 sulfiredoxinIUBMB Comments
In the course of the reaction of EC 1.11.1.15, peroxiredoxin, its cysteine residue is alternately oxidized to the sulfenic acid, S-hydroxycysteine, and reduced back to cysteine. Occasionally the S-hydroxycysteine residue is further oxidized to the sulfinic acid S-hydroxy-S-oxocysteine, thereby inactivating the enzyme. The reductase provides a mechanism for regenerating the active form of peroxiredoxin, i.e. the peroxiredoxin-(S-hydroxycysteine) form. Apparently the reductase first catalyses the phosphorylation of the -S(O)-OH group by ATP to give -S(O)-O-P, which is attached to the peroxiredoxin by a cysteine residue, forming an -S(O)-S- link between the two enzymes. Attack by a thiol splits this bond, leaving the peroxiredoxin as the sulfenic acid and the reductase as the thiol.
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Word Map
- 1.8.98.2
- peroxiredoxins
-
hyperoxidation
- thioredoxins
-
overoxidized
-
sulfenic
-
peroxidatic
- txnrd1
-
sulfinylated
-
deglutathionylation
-
prxiii
-
prdxs
-
cys-so2h
- medicine
- drug development
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
Synonyms
sulfiredoxin, srxn1, sulfiredoxin-1, atsrx, sulfiredoxin 1, sulphiredoxin, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
reduction
ATP-dependent reduction of cysteinesulfinic acid of hyperoxidized peroxiredoxin
reduction
SYSTEMATIC NAME
IUBMB Comments
peroxiredoxin-(S-hydroxy-S-oxocysteine):thiol oxidoreductase [ATP-hydrolysing; peroxiredoxin-(S-hydroxycysteine)-forming]
In the course of the reaction of EC 1.11.1.15, peroxiredoxin, its cysteine residue is alternately oxidized to the sulfenic acid, S-hydroxycysteine, and reduced back to cysteine. Occasionally the S-hydroxycysteine residue is further oxidized to the sulfinic acid S-hydroxy-S-oxocysteine, thereby inactivating the enzyme. The reductase provides a mechanism for regenerating the active form of peroxiredoxin, i.e. the peroxiredoxin-(S-hydroxycysteine) form. Apparently the reductase first catalyses the phosphorylation of the -S(O)-OH group by ATP to give -S(O)-O-P, which is attached to the peroxiredoxin by a cysteine residue, forming an -S(O)-S- link between the two enzymes. Attack by a thiol splits this bond, leaving the peroxiredoxin as the sulfenic acid and the reductase as the thiol.
CAS REGISTRY NUMBER
COMMENTARY
710319-61-2
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 DTT
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + DTT disulfide
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 GSH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + G-S-S-G
combined GSH and H2S for the repair of cytosolic Prx2
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 H2S
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + HS-SH
preference for H2S to support the repair of mitochondrial hyperoxidized Prx3 by Srx. Combined GSH and H2S for the repair of cytosolic Prx2
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 thioredoxin
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + thioredoxin disulfide
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + GSH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + G-S-S-G
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + GSH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + GSSG
identification of intact protein thiosulfinate intermediate in the reduction of cysteine sulfinic acid in peroxiredoxin by human sulfiredoxin
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + GSH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + GSSG
-
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + thioredoxin 1
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + thioredoxin 1 disulfide
-
-
-
-
r
peroxiredoxin-(S-hydroxy-S-oxocysteine) + dATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + dADP + phosphate + R-S-S-R
-
both glutathione and thioredoxin are potential physiological electron donors
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + dGTP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + GDP + phosphate + R-S-S-R
-
both glutathione and thioredoxin are potential physiological electron donors
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + GTP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + GDP + phosphate + R-S-S-R
-
both glutathione and thioredoxin are potential physiological electron donors
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
r
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
repairs the inactivated forms of typical two-Cys peroxiredoxins implicated in hydrogen peroxide-mediated cell signaling
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
the ATP molecule is cleaved between the beta- and gamma-phosphate groups
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
hyperoxidized Prx1
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
-
r
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
antioxidant protein with a role in signaling through catalytic reduction of oxidative modifications. Srx also has a role in the reduction of glutathionylation a post-translational, oxidative modification that occurs on numerous proteins and has been implicated in a wide variety of pathologies, including Parkinsons disease. Unlike the reduction of peroxiredoxin overoxidation, Srx-dependent deglutathionylation appears to be nonspecific
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
Srx is largely responsible for reduction of the Cys-SO2H of peroxiredoxin in A549 human cells
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
both glutathione and thioredoxin are potential physiological electron donors
-
-
?
additional information
?
-
Srx forms a complex with the endoplasmic reticulum-resident protein thioredoxin domain-containing protein 5 (TXNDC5) in vivo and in vitro. TXNDC5 directly interacts with Srx through its thioredoxin-like domains, mapping of the interacting domains between Srx and TXNDC5, the thioredoxin-like domains 1 and 3 are responsible for the binding to Srx, overview. Deletion of the first or third thioredoxin-like domain in TXNDC5 results in a significant loss of its binding to Srx, whereas deletion of the second (the one in the middle) thioredoxin-like domain does not compromise its binding to Srx. The Srx-TXNDC5 is a relatively stable complex that is not affected by the treatment with exogenous H2O2
-
-
-
additional information
?
-
-
Srx forms a complex with the endoplasmic reticulum-resident protein thioredoxin domain-containing protein 5 (TXNDC5) in vivo and in vitro. TXNDC5 directly interacts with Srx through its thioredoxin-like domains, mapping of the interacting domains between Srx and TXNDC5, the thioredoxin-like domains 1 and 3 are responsible for the binding to Srx, overview. Deletion of the first or third thioredoxin-like domain in TXNDC5 results in a significant loss of its binding to Srx, whereas deletion of the second (the one in the middle) thioredoxin-like domain does not compromise its binding to Srx. The Srx-TXNDC5 is a relatively stable complex that is not affected by the treatment with exogenous H2O2
-
-
-
additional information
?
-
specificity of human sulfiredoxin for reductant and peroxiredoxin oligomeric state, overview. The resolution of the Prx-Srx complex involves the reduction of the thiosulfinate intermediate (Prx-CP-S=O-S-Srx) to yield the Prx Cys-sulfenic acid intermediate (Prx-CP-SOH). Yeast Srx contains an adjacent resolving Cys residue (Cys-SR) that can react with the thiosulfinate intermediate leading to the formation of an Srx intramolecular disulfide (Srx-(S-S)). In contrast, human Srx has only one Cys residue and requires an exogenous reductant. Possible reductants include the Trx system (Trx/TrxR/NADPH), glutathione (GSH) and hydrogen sulfide (H2S), these reductants would ultimately yield reduced Srx (Srx-SH). Enzyme-substrate binding studies with mutant Prx1 (e.g. Prx1 C83V and Prx1 C71S/C173S). Repair of hyperoxidized Prx2, Prx3 and their chimeras, the C-terminal sequence differences between Prx2 and Prx3 impact the rate of repair by Srx
-
-
-
additional information
?
-
-
specificity of human sulfiredoxin for reductant and peroxiredoxin oligomeric state, overview. The resolution of the Prx-Srx complex involves the reduction of the thiosulfinate intermediate (Prx-CP-S=O-S-Srx) to yield the Prx Cys-sulfenic acid intermediate (Prx-CP-SOH). Yeast Srx contains an adjacent resolving Cys residue (Cys-SR) that can react with the thiosulfinate intermediate leading to the formation of an Srx intramolecular disulfide (Srx-(S-S)). In contrast, human Srx has only one Cys residue and requires an exogenous reductant. Possible reductants include the Trx system (Trx/TrxR/NADPH), glutathione (GSH) and hydrogen sulfide (H2S), these reductants would ultimately yield reduced Srx (Srx-SH). Enzyme-substrate binding studies with mutant Prx1 (e.g. Prx1 C83V and Prx1 C71S/C173S). Repair of hyperoxidized Prx2, Prx3 and their chimeras, the C-terminal sequence differences between Prx2 and Prx3 impact the rate of repair by Srx
-
-
-
additional information
?
-
Srx transfers the gamma-phosphate of ATP to Cp sulfinic acid on hyperoxidized Prxs and produces sulfinic phosphoryl ester. Subsequent involvement of GSH and thioredoxin will ensure the reduction of sulfinic phosphoryl ester to sulfenic acid
-
-
-
additional information
?
-
-
Srx transfers the gamma-phosphate of ATP to Cp sulfinic acid on hyperoxidized Prxs and produces sulfinic phosphoryl ester. Subsequent involvement of GSH and thioredoxin will ensure the reduction of sulfinic phosphoryl ester to sulfenic acid
-
-
-
additional information
?
-
-
catalyzes the reduction of cysteine sulfinic acid to sulfenic acid in oxidized proteins and protects them from inactivation
-
-
?
additional information
?
-
-
promotes the reversal of cysteine modified PTP1B to its reduced and enzymatically active form
-
-
?
additional information
?
-
-
reduction of cysteine sulfinic acid to sulfenic acid in proteins subject to oxidative stress
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 thioredoxin
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + thioredoxin disulfide
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
repairs the inactivated forms of typical two-Cys peroxiredoxins implicated in hydrogen peroxide-mediated cell signaling
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
antioxidant protein with a role in signaling through catalytic reduction of oxidative modifications. Srx also has a role in the reduction of glutathionylation a post-translational, oxidative modification that occurs on numerous proteins and has been implicated in a wide variety of pathologies, including Parkinsons disease. Unlike the reduction of peroxiredoxin overoxidation, Srx-dependent deglutathionylation appears to be nonspecific
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
-
Srx is largely responsible for reduction of the Cys-SO2H of peroxiredoxin in A549 human cells
-
-
?
additional information
?
-
Srx forms a complex with the endoplasmic reticulum-resident protein thioredoxin domain-containing protein 5 (TXNDC5) in vivo and in vitro. TXNDC5 directly interacts with Srx through its thioredoxin-like domains, mapping of the interacting domains between Srx and TXNDC5, the thioredoxin-like domains 1 and 3 are responsible for the binding to Srx, overview. Deletion of the first or third thioredoxin-like domain in TXNDC5 results in a significant loss of its binding to Srx, whereas deletion of the second (the one in the middle) thioredoxin-like domain does not compromise its binding to Srx. The Srx-TXNDC5 is a relatively stable complex that is not affected by the treatment with exogenous H2O2
-
-
-
additional information
?
-
-
Srx forms a complex with the endoplasmic reticulum-resident protein thioredoxin domain-containing protein 5 (TXNDC5) in vivo and in vitro. TXNDC5 directly interacts with Srx through its thioredoxin-like domains, mapping of the interacting domains between Srx and TXNDC5, the thioredoxin-like domains 1 and 3 are responsible for the binding to Srx, overview. Deletion of the first or third thioredoxin-like domain in TXNDC5 results in a significant loss of its binding to Srx, whereas deletion of the second (the one in the middle) thioredoxin-like domain does not compromise its binding to Srx. The Srx-TXNDC5 is a relatively stable complex that is not affected by the treatment with exogenous H2O2
-
-
-
additional information
?
-
-
catalyzes the reduction of cysteine sulfinic acid to sulfenic acid in oxidized proteins and protects them from inactivation
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4-(((4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid
LMT-328, synthesis, a derivative of Jl4, more potent inhibitor than J14. The simulation, LMT-328 shows fast stabilization and tight binding with Srx. LMT-328 has a similar binding pose as the lead compound, J14, overview
-
4-[[[4-[4-(2-chlorophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid
J14, synthesis, interferes with the antioxidant activity of Srx at the molecular level. Identification of two possible inhibition mechanisms of Srx by J14. Using molecular dynamics simulations and binding free energy calculations, it is confirmed that J14 binds to the ATP binding site, J14 acts as a competitive inhibitor of ATP. J14 can serve as a protein-protein interaction inhibitor that interferes with the binding between Prx and Srx
-
additional information
analysis of the inhibition mechanism of sulfiredoxin using molecular modeling and development of its inhibitors. Protein-ligand docking simulation of J14 and LMT-328, molecular dynamics simulation and binding free energy calculation, elucidation of the Srx inhibition mechanism, detailed overview
-
additional information
-
screening for Srx inhibitors is carried out in an automated setup using 25000 chemicals
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0067
4-(((4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid
Homo sapiens
against A549 cells, pH and temperature not specified in the publication
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
Srx is highly expressed in primary specimen of lung cancer patients
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
colocalization of Srx and TXNDC5 in endoplasmic reticulum of cultured cells
-
cytosolic Srx is translocated into the mitochondria under oxidative conditions
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
additional information
Cys99 of Srx is critical for its catalytic activity
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
-
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SRXN1_HUMAN
137
0
14259
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
the decameric Srx-Prx1 complex reveals extended binding interface, human Prx1 and Prx2 form a decameric toroid
additional information
-
the decameric Srx-Prx1 complex reveals extended binding interface, human Prx1 and Prx2 form a decameric toroid
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystals of the wild-type and SeMet forms of ET-hSrx were obtained by the vapor diffusion method. 1.65 A crystal structure of human Srx
purified Srx-Prx1 complex, hanging drop vapor diffusion method, mixing of 10 mg/ml protein in 20 mM HEPES, pH 7.5, 100 mM NaCl with well solution containing 100 mM citric acid, pH 4.5, 26% PEG 400, and 100 mM CsCl, X-ray diffraction structure determination and analysis at 3.0 A resolution, molecular replacement and modeling by superimposing five dimeric Srx-Prx1 complexes (PDB entry 2RII) onto the five Prx dimers within the decameric Prx2-SO2H (PDB ID 1QMV) structure. The entire active site helix of Prx1 (residues 46-69) and the C-terminus (residues 169-199) are removed from the search model to reduce bias. Two decamers, each containing ten Prx and ten Srx molecules (five Prx dimers and ten Srx monomers), are found in the asymmetric unit, consistent with the observed self-rotation function. Additional crystallization of hyperoxidized Prx2 and Prx3 variants
vapour diffusion method, 2.6 A crystal structure of the sulphiredoxinperoxiredoxin-I complex
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C99A
site-directed mutagenesis, the mutation leads to a complete loss of both Srx enzymatic activity and binding to substrates such as Prxs
C99S
mutant created to show the importance of the cytosine residue in the deglutathionylation function of the protein
C99S
additional information
additional information
several lentiviral shRNAs targeting separate coding regions of Srx mRNA (shSrx) are used to knockdown the levels of endogenously expressed protein. Two shRNAs targeting the coding regions of TXNDC5 have the highest efficiency to inhibit the expression of endogenous protein. These shRNAs are introduced into A549 and H226 cells by viral infection. Enzyme knockdown in in stable A-549 or H-226 cells expressing shSrx1 or shSrx2. Knockdown of Srx leads to a rapid activation of the unfolded protein response (UPR) and sensitizes human lung cancer cells to ER stress-induced cell death
additional information
-
several lentiviral shRNAs targeting separate coding regions of Srx mRNA (shSrx) are used to knockdown the levels of endogenously expressed protein. Two shRNAs targeting the coding regions of TXNDC5 have the highest efficiency to inhibit the expression of endogenous protein. These shRNAs are introduced into A549 and H226 cells by viral infection. Enzyme knockdown in in stable A-549 or H-226 cells expressing shSrx1 or shSrx2. Knockdown of Srx leads to a rapid activation of the unfolded protein response (UPR) and sensitizes human lung cancer cells to ER stress-induced cell death
additional information
Srx mutant variants analyzed by circular dichroism spectroscopy (JASCO-720) in 20 mM HEPES, pH 7.5, 100 mM NaCl at a concentration from 0.4 mg/ml are confirmed to exhibit wild-type-like spectra
additional information
-
Srx mutant variants analyzed by circular dichroism spectroscopy (JASCO-720) in 20 mM HEPES, pH 7.5, 100 mM NaCl at a concentration from 0.4 mg/ml are confirmed to exhibit wild-type-like spectra
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
His-Srx proteins are purified from cell lysates by chromatography on a column on Ni-chelating Sepharose
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
transient recombinant expression of the FLAG-tagged enzyme in different cell types, including HEK293T, H226, and A549 cells, recombinant expression of FLAG-tagged Srx mutant C99A mutant in HEK-293T cells. The Srx-protein complex is pulled down by anti-FLAG immunoprecipitation (IP), and protein identities are determined by mass spectrometry. Among the handful of proteins identified, Prx4 is the most abundant protein, and TXNDC5 is the second most abundant protein that is specifically pulled down by anti-FLAG IP in all cell types. c-Myc-tagged TXNDC5 or its cysteine-specific mutants are expressed in HEK-293T-FLAG-Srx cells
the 5' flanking region of the human Srx1 promoter region, -3664 - +19, is ligated into the vector pCR2.1
-
the vectors pcDNA3 and pFLAG-CMV2 are used, a leader sequence is cloned into the N-terminus coding region of Srx
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
Nrf2, nuclear factor erythroid-2-related factor, up-regulates Srx1 expression during oxidative stress caused by cigarette smoke exposure in the lungs
-
oxidative stress and growth factors can markedly upregulate Srx transcript and protein levels
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
the lung cancer patients with high Srx levels have significantly shorter survival and those with high TXNDC5 levels have longer survival. Cellular levels of Srx and TXNDC5 may be useful as biomarkers to predict the survival of individuals with lung cancer
drug development
-
Srx may be a potential target for prevention or treatment of cancer, the colorimetric assay would be useful for high-throughput screening of Srx inhibitors as demonstrated
medicine
medicine
-
increased sulfiredoxin has been linked with oncogenic transformation, data support a role for Srx in controlling the phosphorylation status of key regulatory kinases
medicine
-
oxidative stress results in protein oxidation and is involved in the pathogenesis of lung diseases such as chronic obstructive pulmonary disorder, COPD, in lungs from COPD patients the expression of Srx1 is dramatically decreased
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Jnsson, T.J.; Murray, M.S.; Johnson, L.C.; Poole, L.B.; Lowther, W.T.
Structural basis for the retroreduction of inactivated peroxiredoxins by human sulfiredoxin
Biochemistry
44
8634-8642
2005
Homo sapiens (Q9BYN0), Homo sapiens
Findlay, V.J.; Tapiero, H.; Townsend, D.M.
Sulfiredoxin: a potential therapeutic agent?
Biomed. Pharmacother.
59
374-379
2005
Homo sapiens
Chang, T.S.; Jeong, W.; Woo, H.A.; Lee, S.M.; Park, S.; Rhee, S.G.
Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine
J. Biol. Chem.
279
50994-51001
2004
Homo sapiens, Mus musculus, Rattus norvegicus
Lee, D.Y.; Park, S.J.; Jeong, W.; Sung, H.J.; Oho, T.; Wu, X.; Rhee, S.G.; Gruschus, J.M.
Mutagenesis and modeling of the peroxiredoxin (Prx) complex with the NMR structure of ATP-bound human sulfiredoxin implicate aspartate 187 of Prx I as the catalytic residue in ATP hydrolysis
Biochemistry
45
15301-15309
2006
Homo sapiens (Q9BYN0), Homo sapiens
Findlay, V.J.; Townsend, D.M.; Morris, T.E.; Fraser, J.P.; He, L.; Tew, K.D.
A novel role for human sulfiredoxin in the reversal of glutathionylation
Cancer Res.
66
6800-6806
2006
Homo sapiens (Q9BYN0), Homo sapiens
Jeong, W.; Park, S.J.; Chang, T.S.; Lee, D.Y.; Rhee, S.G.
Molecular mechanism of the reduction of cysteine sulfinic acid of peroxiredoxin to cysteine by mammalian sulfiredoxin
J. Biol. Chem.
281
14400-14407
2006
Homo sapiens
Jang, H.H.; Chi, Y.H.; Park, S.K.; Lee, S.S.; Lee, J.R.; Park, J.H.; Moon, J.C.; Lee, Y.M.; Kim, S.Y.; Lee, K.O.; Lee, S.Y.
Structural and functional regulation of eukaryotic 2-Cys peroxiredoxins including the plant ones in cellular defense-signaling mechanisms against oxidative stress
Physiol. Plant.
126
549-559
2006
Saccharomyces cerevisiae, Homo sapiens
Joensson, T.J.; Tsang, A.W.; Lowther, W.T.; Furdui, C.M.
Identification of intact protein thiosulfinate intermediate in the reduction of cysteine sulfinic acid in peroxiredoxin by human sulfiredoxin
J. Biol. Chem.
283
22890-22894
2008
Homo sapiens (Q9BYN0), Homo sapiens
Joensson, T.J.; Johnson, L.C.; Lowther, W.T.
Structure of the sulphiredoxin-peroxiredoxin complex reveals an essential repair embrace
Nature
451
98-101
2008
Homo sapiens (Q9BYN0), Homo sapiens
Kim, H.; Kim, H.; Hong, S.; Rhee, S.G.; Jeong, W.
A colorimetric assay for sulfiredoxin activity using inorganic phosphate measurement
Anal. Biochem.
393
36-40
2009
Homo sapiens
Singh, A.; Ling, G.; Suhasini, A.N.; Zhang, P.; Yamamoto, M.; Navas-Acien, A.; Cosgrove, G.; Tuder, R.M.; Kensler, T.W.; Watson, W.H.; Biswal, S.
Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs
Free Radic. Biol. Med.
46
376-386
2009
Homo sapiens, Mus musculus
Park, J.W.; Mieyal, J.J.; Rhee, S.G.; Chock, P.B.
Deglutathionylation of 2-Cys peroxiredoxin is specifically catalyzed by sulfiredoxin
J. Biol. Chem.
284
23364-23374
2009
Homo sapiens
Noh, Y.H.; Baek, J.Y.; Jeong, W.; Rhee, S.G.; Chang, T.S.
Sulfiredoxin Translocation into Mitochondria Plays a Crucial Role in Reducing Hyperoxidized Peroxiredoxin III
J. Biol. Chem.
284
8470-8477
2009
Homo sapiens
Lei, K.; Townsend, D.M.; Tew, K.D.
Protein cysteine sulfinic acid reductase (sulfiredoxin) as a regulator of cell proliferation and drug response
Oncogene
27
4877-4887
2008
Homo sapiens
Forshaw, T.E.; Reisz, J.A.; Nelson, K.J.; Gumpena, R.; Lawson, J.R.; Joensson, T.J.; Wu, H.; Clodfelter, J.E.; Johnson, L.C.; Furdui, C.M.; Lowther, W.T.
Specificity of human sulfiredoxin for reductant and peroxiredoxin oligomeric state
Antioxidants (Basel)
10
946
2021
Homo sapiens (Q9BYN0), Homo sapiens
Chawsheen, H.A.; Jiang, H.; Ying, Q.; Ding, N.; Thapa, P.; Wei, Q.
The redox regulator sulfiredoxin forms a complex with thioredoxin domain-containing 5 protein in response to ER stress in lung cancer cells
J. Biol. Chem.
294
8991-9006
2019
Homo sapiens (Q9BYN0), Homo sapiens
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