Information on EC 1.8.98.2 - sulfiredoxin

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY hide
1.8.98.2
-
RECOMMENDED NAME
GeneOntology No.
sulfiredoxin
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH = peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
show the reaction diagram
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-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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 hide
710319-61-2
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
overoxidized human peroxiredoxin V + reduced thioredoxin
? + oxidized thioredoxin
show the reaction diagram
Arabidopsis enzyme is able to reduce overoxidized human Prx V
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 DTT
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + DTT disulfide
show the reaction diagram
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 GSH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + G-S-S-G
show the reaction diagram
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
show the reaction diagram
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 thioredoxin
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + thioredoxin disulfide
show the reaction diagram
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + GSH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + GSSG
show the reaction diagram
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
show the reaction diagram
peroxiredoxin-(S-hydroxy-S-oxocysteine) + dATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + dADP + phosphate + R-S-S-R
show the reaction diagram
-
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
show the reaction diagram
-
both glutathione and thioredoxin are potential physiological electron donors
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + dGTP + R-SH
peroxiredoxin-(S-hydroxycysteine) + GDP + phosphate + R-S-S-R
show the reaction diagram
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formation of a covalent thiosulfinate peroxiredoxin-sulfiredoxin species as an intermediate on the catalytic pathway
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + gamma-S-ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + thiophosphate + R-S-S-R
show the reaction diagram
-
-
-
-
?
peroxiredoxin-(S-hydroxy-S-oxocysteine) + GTP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + GDP + phosphate + R-S-S-R
show the reaction diagram
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both glutathione and thioredoxin are potential physiological electron donors
-
-
?
sulfinic form of peroxiredoxin IIF + oxidized thioredoxin
? + reduced thioredoxin
show the reaction diagram
in mitochondria, sulfiredoxin catalyzes the retroreduction of the inactive sulfinic form of atypical peroxiredoxin IIF using thioredoxin as reducing agent
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-
?
sulfinic form of peroxiredoxin IIF + reduced thioredoxin
? + oxidized thioredoxin
show the reaction diagram
in mitochondria, sulfiredoxin catalyzes the retroreduction of the inactive sulfinic form of atypical peroxiredoxin IIF using thioredoxin as reducing agent
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-
?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
show the reaction diagram
peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + R-SH
peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R
show the reaction diagram
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
dithiothreitol
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-
glutathione
-
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thioredoxin
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
siRNA
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-
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additional information
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screening for Srx inhibitors is carried out in an automated setup using 25000 chemicals
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.03 - 0.125
ATP
0.13
gamma-S-ATP
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pH 7.0, 30°C
1.8
GSH
-
-
0.029 - 0.079
peroxiredoxin-(S-hydroxy-S-oxocysteine)
0.0012
thioredoxin 1
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additional information
additional information
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kinetic analysis, overview
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.03
ATP
Saccharomyces cerevisiae
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wild-type, pH 7.0, 30°C
0.016
gamma-S-ATP
Saccharomyces cerevisiae
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wild-type, pH 7.0, 30°C
0.00042 - 0.011
peroxiredoxin-(S-hydroxy-S-oxocysteine)
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
23
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malachite green assay at room temperature
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
9.86
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mature enzyme, sequence calculation
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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cortical glial cell, in both neurons and glia, Nrf2 expression and treatment with chemopreventive Nrf2 activators, including 3H-1,2-dithiole-3-thione and sulforaphane, upregulate sulfiredoxin, an enzyme responsible for reducing hyperoxidized peroxiredoxins
Manually annotated by BRENDA team
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cortical neuron, in both neurons and glia, Nrf2 expression and treatment with chemopreventive Nrf2 activators, including 3H-1,2-dithiole-3-thione and sulforaphane, upregulate sulfiredoxin, an enzyme responsible for reducing hyperoxidized peroxiredoxins
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
12000
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SDS-PAGE
14000
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-
15000
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Srx monomer, determined by SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
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vapour diffusion method, 2.6 A crystal structure of the sulphiredoxin–peroxiredoxin-I complex
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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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Ni2+-NTA column chromatography
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recombinant wild-type Srx and mutants to homogeneity from Escherichia coli strain BL21(DE3) by nickel affinity and anion exchange chromatography
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
DNA and amino acid sequence determination and analysis, expression of N-terminally His6-tagged wild-type Srx and mutants in Escherichia coli strain BL21(DE3)
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expressed in HEK293 cells and Escherichia coli
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expressed in Saccharomyces cerevisiae
expression in Escherichia coli
for expression in Escherichia coli BL21DE3 cells
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into the vector pcDNA3
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into the vector pET14b for expression in Escherichia coli BL21 cells
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the 5' flanking region of the human Srx1 promoter region, -3664 - +19, is ligated into the vector pCR2.1
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the vectors pcDNA3 and pFLAG-CMV2 are used, a leader sequence is cloned into the N-terminus coding region of Srx
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transient expression of an AtSrx-GFP fusion in Nicotiana tabacum leaves
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
disruption of Nrf2 signaling down-regulates the expression of Srx1
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
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E76A
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site-directed mutagenesis, the mutant shows increased activity compared to the wild-type enzyme
K40Q
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site-directed mutagenesis, the mutant shows decreased activity compared to the wild-type enzyme
R28Q
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site-directed mutagenesis, the mutant shows decreased activity compared to the wild-type enzyme
R28Q/E76A
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site-directed mutagenesis, inactive mutant
C72S
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site-directed mutagenesis, the mutant shows decreased activity compared to the wild-type enzyme
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E76A
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site-directed mutagenesis, the mutant shows increased activity compared to the wild-type enzyme
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R28Q
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site-directed mutagenesis, the mutant shows decreased activity compared to the wild-type enzyme
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R28Q/E76A
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site-directed mutagenesis, inactive mutant
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C99A
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Cys99 replaced by Ala
D57N
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Asp57 replaced by Asn
D79N
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Asp60 replaced by Asn
H100N
-
Srx mutant
H99N
-
His99 replaced by Asn
K60R
-
Lys60 replaced by Arg
R100M
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Arg100 replaced by Met
R101M
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Srx mutant
R50M
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Arg50 replaced by Met
Y92R
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Srx mutant
C106A
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mutant, constructed to address questions regarding the catalytic mechanisms and the role of the cysteine residues
C48A
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mutant, constructed to address questions regarding the catalytic mechanisms and the role of the cysteine residues
C48A/C106A
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mutant, constructed to address questions regarding the catalytic mechanisms and the role of the cysteine residues
C84S
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Srx1 reactivates the yeast Prx1 peroxidase activity that is inactivated by H2O2. Mutant C84S does not induce the reactivation of inactivated Prx1 or dissociation of the high molecular weight Prx1 complex
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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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
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