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Information on EC 1.11.1.27 - glutathione-dependent peroxiredoxin and Organism(s) Homo sapiens and UniProt Accession P30041

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EC Tree
     1 Oxidoreductases
         1.11 Acting on a peroxide as acceptor
             1.11.1 Peroxidases
                1.11.1.27 glutathione-dependent peroxiredoxin
IUBMB Comments
Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant proteins. They can be divided into three classes: typical 2-Cys, atypical 2-Cys and 1-Cys peroxiredoxins . The peroxidase reaction comprises two steps centred around a redox-active cysteine called the peroxidatic cysteine. All three peroxiredoxin classes have the first step in common, in which the peroxidatic cysteine attacks the peroxide substrate and is oxidized to S-hydroxycysteine (a sulfenic acid) (see {single/111115a::mechanism}). The second step of the peroxidase reaction, the regeneration of cysteine from S-hydroxycysteine, distinguishes the three peroxiredoxin classes. For typical 2-Cys Prxs, in the second step, the peroxidatic S-hydroxycysteine from one subunit is attacked by the 'resolving' cysteine located in the C-terminus of the second subunit, to form an intersubunit disulfide bond, which is then reduced by one of several cell-specific thiol-containing reductants completing the catalytic cycle. In the atypical 2-Cys Prxs, both the peroxidatic cysteine and its resolving cysteine are in the same polypeptide, so their reaction forms an intrachain disulfide bond. The 1-Cys Prxs conserve only the peroxidatic cysteine, so its regeneration involves direct interaction with a reductant molecule. Glutathione-dependent peroxiredoxins have been reported from bacteria and animals, and appear to be 1-Cys enzymes. The mechanism for the mammalian PRDX6 enzyme involves heterodimerization of the enzyme with pi-glutathione S-transferase, followed by glutathionylation of the oxidized cysteine residue. Subsequent dissociation of the heterodimer yields glutathionylated peroxiredoxin, which is restored to the active form via spontaneous reduction by a second glutathione molecule.
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Homo sapiens
UNIPROT: P30041
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
peroxiredoxin vi, pf1-cys-prx, 1-cys prdx, hi0572, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
1-Cys Prx
-
glutathione peroxidase
-
peroxiredoxin 6
peroxiredoxin VI
-
1-Cys Prdx
-
-
peroxiredoxin 6
-
-
Prdx6
Prx3
-
-
-
-
PATHWAY SOURCE
PATHWAYS
SYSTEMATIC NAME
IUBMB Comments
glutathione:hydroperoxide oxidoreductase
Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant proteins. They can be divided into three classes: typical 2-Cys, atypical 2-Cys and 1-Cys peroxiredoxins [1]. The peroxidase reaction comprises two steps centred around a redox-active cysteine called the peroxidatic cysteine. All three peroxiredoxin classes have the first step in common, in which the peroxidatic cysteine attacks the peroxide substrate and is oxidized to S-hydroxycysteine (a sulfenic acid) (see {single/111115a::mechanism}). The second step of the peroxidase reaction, the regeneration of cysteine from S-hydroxycysteine, distinguishes the three peroxiredoxin classes. For typical 2-Cys Prxs, in the second step, the peroxidatic S-hydroxycysteine from one subunit is attacked by the 'resolving' cysteine located in the C-terminus of the second subunit, to form an intersubunit disulfide bond, which is then reduced by one of several cell-specific thiol-containing reductants completing the catalytic cycle. In the atypical 2-Cys Prxs, both the peroxidatic cysteine and its resolving cysteine are in the same polypeptide, so their reaction forms an intrachain disulfide bond. The 1-Cys Prxs conserve only the peroxidatic cysteine, so its regeneration involves direct interaction with a reductant molecule. Glutathione-dependent peroxiredoxins have been reported from bacteria and animals, and appear to be 1-Cys enzymes. The mechanism for the mammalian PRDX6 enzyme involves heterodimerization of the enzyme with pi-glutathione S-transferase, followed by glutathionylation of the oxidized cysteine residue. Subsequent dissociation of the heterodimer yields glutathionylated peroxiredoxin, which is restored to the active form via spontaneous reduction by a second glutathione molecule.
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
1-palmitoyl-2-arichidonoyl-sn-glycero-3-phosphocholine + GSH
?
show the reaction diagram
-
-
-
?
1-palmitoyl-2-linolenoyl-sn-glycero-3-phosphocholine hydroperoxide + GSH
?
show the reaction diagram
-
-
-
?
2 glutathione + H2O2
glutathione disulfide + 2 H2O
show the reaction diagram
-
-
-
?
2 glutathione + ROOH
glutathione disulfide + H2O + ROH
show the reaction diagram
-
-
-
?
arachidonoyl hydroperoxide + GSH
?
show the reaction diagram
-
-
-
?
cumene hydroperoxide + GSH
2-phenylpropan-2-ol + GSSG
show the reaction diagram
-
-
-
?
H2O2 + dithiothreitol
?
show the reaction diagram
-
-
-
?
H2O2 + GSH
H2O + GSSG
show the reaction diagram
-
-
-
?
linolenoyl hydroperoxide + GSH
?
show the reaction diagram
-
-
-
?
tert-butyl hydroperoxide + GSH
tert-butanol + GSSG
show the reaction diagram
-
-
-
?
2 GSH + ROOH
GSSG + H2O + ROH
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2 glutathione + H2O2
glutathione disulfide + 2 H2O
show the reaction diagram
-
-
-
?
2 glutathione + ROOH
glutathione disulfide + H2O + ROH
show the reaction diagram
-
-
-
?
2 GSH + ROOH
GSSG + H2O + ROH
show the reaction diagram
-
glutathione is the primary native reductant
-
-
?
additional information
?
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
withangulatin A
-
-
Mercaptosuccinate
-
a thiol-active agent that inhibits the peroxidase activity of Prdx6 while the PLA2 activity is unaffected
MJ33
-
a phospholipid substrate intermediate analogue, inhibits the PLA2 activity of Prdx6 but has no effect on peroxidase activity
additional information
-
serine protease inhibitors inhibit the PLA2 activity of Prdx6 but have no effect on peroxidase activity
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.129
1-palmitoyl-2-arichidonoyl-sn-glycero-3-phosphocholine
-
0.12
1-palmitoyl-2-linolenoyl-sn-glycero-3-phosphocholine hydroperoxide
-
0.135
arachidonoyl hydroperoxide
-
0.12
cumene hydroperoxide
-
0.18
H2O2
-
0.141
linolenoyl hydroperoxide
-
0.142
tert-butyl hydroperoxide
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00118
withangulatin A
Homo sapiens
pH and temperature not specified in the publication
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 10
about 40% activity at pH 6.0, 100% activity at pH 7.0, about 90% activity at pH 8.0, about 70% activity at pH 9.0, about 60% activity at pH 10.0
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
especially in type II alveolar epithelial cells and bronchiolar Clara cells
Manually annotated by BRENDA team
additional information
-
within organs, expression of Prdx is greatest in epithelium such as apical regions of respiratory epithelium and skin epidermis, tissue distribution, overview
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
cytosolic Prdx6 could bind to and reduce peroxidized membrane phospholipids followed by its dissociation from the membrane and return to the cytosolic compartment
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
peroxiredoxin 6 down-regulation reduces cell proliferation. Enzyme silencing interferes with apoptotic signaling from CD95 but does not induce apoptosis in HepG2 cells
physiological function
physiological function
-
Prdx6 has important roles in both antioxidant defense based on its ability to reduce peroxidized membrane phospholipids and in phospholipid homeostasis based on its ability to generate lysophospholipid substrate for the remodeling pathway of phospholipid synthesis
additional information
-
regulation of Prdx6 gene regulation, overview. Transcription is activated by binding of the transcription factor Nrf2 to the ARE whereas transcription is inhibited by the binding of Nrf3. Prdx6 expression also is responsive to hormonal regulation
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
PRDX6_HUMAN
224
0
25035
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25034
x * 25034, calculation from nucleotide sequence
26000
gel filtration
27000
x * 27000, SDS-PAGE
52000
gel filtration
25100
-
x * 25100, about, sequence calculation, x * 26000-29000, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer or dimer
1 or 2 * 26000, reduced Prdx6 is monomeric while oxidized form is dimeric, SDS-PAGE
?
-
x * 25100, about, sequence calculation, x * 26000-29000, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
-
MAP kinase mediated phosphorylation of Prdx6 at residue T177, results in increased phospholipase A2 activity, but phosphorylation has no effect on the peroxidase activity of Prdx6
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
X-ray diffraction structure determination and analysis at 2.0 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C47S
mutation abolishes peroxidase activity,mutation has no effect on lipase activity
C91S
mutation has no effect on lipase activity
S32A
mutation has no effect on lipase activity
S32G
mutation has no effect on lipase activity
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4 - 7
the enzyme is thermodynamically more stable at pH 4.0 than at pH 7.0. Enzyme at pH 4.0 is resistant to thermal denaturation
765792
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA agarose column chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli M15 [pREP4] cells
expressed in Escherichia coli M15[pREP4] cells
expression in Escherichia coli
expression in Escherichia coli or in NIH 3T3 cells
DNA and amino acid sequence determination, analysis, and comparison
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
PRDX6 levels are decreased during osteogenic differentiation in human dental pulp stem cells
oxidant stress is, e.g. by H2O2, paraquat, a potent inducer of Prdx6 expression and stimulates Prdx6 gene expression by a transcriptional mechanism involving its antioxidant response element, ARE
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
regulating PRDX6 may improve the clinical utility of stem cell-based regenerative medicine for the treatment of bone diseases
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Merkulova, M.I.; Shuvaeva, T.M.; Radchenko, V.V.; Yanin, B.A.; Bondar, A.A.; Sofin, A.D.; Lipkin, V.M.
Recombinant human peroxiredoxin VI: preparation and protective properties in vitro
Biochemistry
67
1235-1239
2002
Homo sapiens (P30041), Homo sapiens
Manually annotated by BRENDA team
Kang, S.W.; Baines, I.C.; Rhee, S.G.
Characterization of a mammalian peroxiredoxin that contains one conserved cysteine
J. Biol. Chem.
273
6303-6311
1998
Homo sapiens (P30041)
Manually annotated by BRENDA team
Manevich, Y.; Fisher, A.B.
Peroxiredoxin 6, a 1-Cys peroxiredoxin, functions in antioxidant defense and lung phospholipid metabolism
Free Radic. Biol. Med.
38
1422-1432
2005
Bos taurus (O77834), Homo sapiens (P30041), Mus musculus (O08709), Rattus norvegicus (O35244), Sus scrofa (Q9TSX9)
Manually annotated by BRENDA team
Fisher, A.B.
Peroxiredoxin 6: A bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities
Antioxid. Redox Signal.
15
831-844
2010
Bos taurus, Homo sapiens, Mus musculus, Rattus norvegicus
Manually annotated by BRENDA team
Park, K.R.; Yun, H.M.; Yeo, I.J.; Cho, S.; Hong, J.T.; Jeong, Y.S.
Peroxiredoxin 6 inhibits osteogenic differentiation and bone formation through human dental pulp stem cells and induces delayed bone development
Antioxid. Redox Signal.
30
1969-1982
2019
Homo sapiens (P30041)
Manually annotated by BRENDA team
Arevalo, J.A.; Vazquez-Medina, J.P.
The role of peroxiredoxin 6 in cell signaling
Antioxidants (Basel)
7
172
2018
Mus musculus (O08709), Homo sapiens (P30041)
Manually annotated by BRENDA team
Lopez Grueso, M.J.; Tarradas Valero, R.M.; Carmona-Hidalgo, B.; Lagal Ruiz, D.J.; Peinado, J.; McDonagh, B.; Requejo Aguilar, R.; Barcena Ruiz, J.A.; Padilla Pena, C.A.
Peroxiredoxin 6 down-regulation induces metabolic remodeling and cell cycle arrest in HepG2 cells
Antioxidants (Basel)
8
505
2019
Homo sapiens (P30041)
Manually annotated by BRENDA team
Chen, C.; Gong, L.; Liu, X.; Zhu, T.; Zhou, W.; Kong, L.; Luo, J.
Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer
Redox Biol.
46
102130
2021
Homo sapiens (P30041)
Manually annotated by BRENDA team
Chowhan, R.K.; Rahaman, H.; Singh, L.R.
Structural basis of peroxidase catalytic cycle of human Prdx6
Sci. Rep.
10
17416
2020
Homo sapiens (P30041)
Manually annotated by BRENDA team
Chowhan, R.K.; Hotumalani, S.; Rahaman, H.; Singh, L.R.
pH induced conformational alteration in human peroxiredoxin 6 might be responsible for its resistance against lysosomal pH or high temperature
Sci. Rep.
11
9657
2021
Homo sapiens (P30041)
Manually annotated by BRENDA team