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Information on EC 1.11.1.12 - phospholipid-hydroperoxide glutathione peroxidase and Organism(s) Rattus norvegicus and UniProt Accession P36970
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1.11.1.12 phospholipid-hydroperoxide glutathione peroxidaseIUBMB Comments
A protein containing a selenocysteine residue. The products of action of EC 1.13.11.12 lipoxygenase on phospholipids can act as acceptors; H2O2 can also act, but much more slowly (cf. EC 1.11.1.9 glutathione peroxidase).
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Word Map
- 1.11.1.12
-
selenoproteins
-
ferroptosis
- gsh
- thioredoxin
- testis
-
iron-dependent
- selenite
- dismutase
- malondialdehyde
- catalase
-
selenoenzyme
- sod
-
hepatokine
-
micronutrient
-
iodothyronine
-
deiodinase
- selenomethionine
-
se-deficient
-
selenium-containing
-
erastin
-
secis
-
selenium-deficient
-
non-apoptotic
-
ferrostatin-1
- spermatozoa
-
se-dependent
-
se-adequate
-
apoer2
- analysis
- na2seo3
-
midpiece
-
selenocysteine-containing
-
se-containing
-
slc7a11
- medicine
-
ferroptosis-related
- 5'-deiodinase
- deferoxamine
-
selenocompounds
- 15-lipoxygenase
- ebselen
- txnrd1
-
hydroperoxy
- gsh-px
- torula
-
peroxidase-1
-
se-enriched
-
biomembranes
-
loohs
-
iron-mediated
-
liver-derived
-
hydroperoxidase
The taxonomic range for the selected organisms is: Rattus norvegicus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
selenoprotein p, phgpx, glutathione peroxidase 4, phospholipid hydroperoxide glutathione peroxidase, gpx-4, glutathione peroxidase-4, npgpx, selenoperoxidase, gpx4b, gpx4a, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
PHGPX
phospholipid hydroperoxide glutathione peroxidase
hydroperoxide glutathione peroxidase
-
-
-
-
peroxidation-inhibiting protein
-
-
-
-
peroxidation-inhibiting protein: peroxidase, glutathione (phospholipid hydroperoxide-reducing)
-
-
-
-
PHGPX
phospholipid hydroperoxide glutathione peroxidase
PHGPX
-
-
-
-
phospholipid hydroperoxide glutathione peroxidase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
reduction
oxidation
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
glutathione:lipid-hydroperoxide oxidoreductase
A protein containing a selenocysteine residue. The products of action of EC 1.13.11.12 lipoxygenase on phospholipids can act as acceptors; H2O2 can also act, but much more slowly (cf. EC 1.11.1.9 glutathione peroxidase).
CAS REGISTRY NUMBER
COMMENTARY
97089-70-8
-
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
2 glutathione + a hydroperoxy-fatty-acyl-[lipid]
glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O
-
-
-
?
2 glutathione + tert-butyl hydroperoxide
glutathione disulfide + tert-butyl hydroxide + H2O
-
-
-
?
glutathione + 3beta-hydroxycholest-5-ene-7alpha-hydroperoxide
cholest-5-ene-3beta,7alpha-diol + ?
-
-
-
-
?
glutathione + a lipid hydroperoxide
glutathione disulfide + lipid + H2O
-
-
-
-
?
glutathione + L-alpha-phosphatidylcholine hydroperoxide
?
-
-
-
-
?
glutathione + lipid hydroperoxide
glutathione disulfide + lipid + H2O
-
-
-
-
?
glutathione + lipid hydroperoxide
glutathione disulfide + lipid + H2O
-
dithiothreitol and dithioerythritol are 3fold more active than glutathione, while 2-mercaptoethanol and L-cysteine show 50% and 20% of the activity with glutathione as reductants, respectively
-
-
?
glutathione + lipid hydroperoxide
glutathione disulfide + lipid + H2O
-
protection of biomembranes against oxidative damage
-
-
?
additional information
?
-
total GPx activity is determined in a photometric NADPH-coupled assay using tert-BHP as the substrate. The decrease of NADPH absorbance is monitored at 340 nm
-
-
-
additional information
?
-
-
reduces hydroxyperoxide derivatives of phospholipids into alcohol derivatives
-
-
?
additional information
?
-
-
enzyme inhibits lipid peroxidation, which is induced by Fe3+-triethylenetetramine complex, NADPH and ascorbate in presence of glutathione, therefore a physiological amount of alpha-tocopherol, vitamin E, is necessary in the membranes
-
-
?
additional information
?
-
-
mitochondrial enzyme inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis
-
-
?
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
2 glutathione + a hydroperoxy-fatty-acyl-[lipid]
glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O
-
-
-
?
glutathione + a lipid hydroperoxide
glutathione disulfide + lipid + H2O
-
-
-
-
?
glutathione + lipid hydroperoxide
glutathione disulfide + lipid + H2O
-
-
-
-
?
glutathione + lipid hydroperoxide
glutathione disulfide + lipid + H2O
-
protection of biomembranes against oxidative damage
-
-
?
additional information
?
-
-
enzyme inhibits lipid peroxidation, which is induced by Fe3+-triethylenetetramine complex, NADPH and ascorbate in presence of glutathione, therefore a physiological amount of alpha-tocopherol, vitamin E, is necessary in the membranes
-
-
?
additional information
?
-
-
mitochondrial enzyme inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Se
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1S,3R)-RSL3
a selective GPx4 inhibitor, causes a decrease in intracellular ATP levels after 24 h in primary pancreatic rat islets
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ferrostatin-1
along with the prevention of beta-cell death, siGPx4-mediated induction of lipid peroxidation and ATP depletion are reduced significantly in the presence of ferroptosis inhibitor ferrostatin-1 at 0.001 mM
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.3
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM KKSQCCQQKT as substrate
0.4
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM KPPCCPPK as substrate
13.6
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM PKSPCCPPKP as substrate
160.2
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM PPCCPP as substrate
25.2
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM PPKPCCPPKP as substrate
28.3
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM PKPPCCPPKP as substrate
36
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM QKSPCCPKSP as substrate
37.5
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM QKPPCCPKSP as substrate
42
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM PKSPCCPPKS as substrate
69
in 0.1 M potassium phosphate, pH 7.8 with 1 mM EDTA, using 0.1 mM PPPPCCPPPP as substrate
0.051
-
enzyme from tissue lysate, using L-alpha-phosphatidylcholine hydroperoxide as peroxide substrate, at 37°C
21.5
-
enzyme after 422fold purification, using L-alpha-phosphatidylcholine hydroperoxide as peroxide substrate, at 37°C
additional information
additional information
-
specific activity of cytosolic and mitochondrial enzymes with several hydroperoxide substrates and reducing agents
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
in the blastomeres, Gpx4 granules are formed, and in the blastocysts, even clusters are present mainly around the cell nuclei
in the blastomeres, Gpx4 granules are formed, and in the blastocysts, even clusters are present mainly around the cell nuclei
endogenous GPX4 is mainly expressed in neurons, usage of primary cultured cortical neurons
Gpx4 is found inside the ovary in the corpus luteum, stroma, follicles, and blood vessels
the enzyme is present in the epithelium, stroma, blood vessels, and smooth muscles of oviduct
insulin-producing beta-cells and primary islets. Pancreatic beta-cells are endowed with a unique high expression level of GPx4, while GPx4 expression is significantly lower in insulin-producing RINm5F cells
assessment of GPx4 expression in different pancreatic islet cell types reveals a predominant expression in beta-cells
Gpx4 is found in the endometrium, myometrium, blood vessels, and stroma of uterus
-
basophil leucemia cell line S1 wild-type cell line and (RBL)2H3 cell line overexpressing mitochondrial phospholipid hydroperoxide glutathione peroxidase
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100 nM 8(S/R)-hydroxy-11(S),12S-trans-epoxyeicosa-5Z,9E,14Z-trienoic acid upregulates phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA and protein expressions. Under persistent oxidative stress the formation of 8(S/R)-hydroxy-11(S),12S-trans-epoxyeicosa-5Z,9E,14Z-trienoic acid and the 8(S/R)-hydroxy-11(S),12S-trans-epoxyeicosa-5Z,9E,14Z-trienoic acid-induced upregulation of PHGPx constitute a compensatory defense response to protect the vitality and functionality of the cell
additional information
In situ RT-PCR analyses of GPx4 in rat pancreas sections, immunohistochemic analysis
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strongly linked to mitochondria of cells undergoing differentiation to spermatozoa, under gonadotropin control
-
treatment with testosterone slightly decreases PHGPx mRNA levels in testes by the reverse transcription-polymerase chain reaction. Anti-androgenic compounds (flutamide, ketoconazole, and diethylhexyl phthalate) and estrogenic compounds (nonylphenol, octylphenol, and diethylstilbestrol) significantly upregulate PHGPx mRNA in the testes. Endocrine disrupting chemicals might have a detrimental effect on spermatogenesis via abnormal enhancement of PHGPx expression in testes
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
beta-cell toxic cytokines did not induce ferroptosis although beta-cells underwent cell death. Inhibition of iNOS by Nomega-nitro-L-arginine however led to a massive lipid peroxidation upon exposure to pro-inflammatory cytokines. Hence, nitric oxide produced during pro-inflammatory cytokine action prevents the induction of ferroptosis, thereby favouring apoptosis as a primary cell death mechanism. The extraordinarily high abundance of the phospholipid hydroperoxidase GPx4 in beta-cells in contrast to the very low expression in other islet cell types points to a susceptibility of beta-cells to the accumulation of toxic lipid peroxides. No involvement of ferroptosis as an alternative beta-cell death mode under pro-inflammatory cytokine attack
physiological function
malfunction
decrease of GPX4 expression potentially plays an important role in ferroptosis during early brain injury after SAH. Overexpression of GPX4 significantly reduces lipid peroxidation and cell death in the experimental SAH models both in vivo. Overexpression of GPX4 has a neuroprotective effect after SAH. Overexpression of GPX4 ameliorates brain edema and neurological deficits at 24 h after SAH
malfunction
silencing of GPx4 by RNA interference and exposure to tert-butyl hydroperoxide (tert-BHP) causes ferroptosis in rat pancreatic beta-cells as evidenced by non-apoptotic cell death in association with increased lipid peroxidation, disturbs ATP synthesis, and reduces GSH content and GPx4 degradation. GPx4 overexpression as well as the ferroptosis inhibitor ferrostatin-1 effectively attenuate beta-cell death induced by tert-BHP. siGPx4- transfected INS-1E cells start to die 96 h post-transfection due to GPx4 deficiency, overview. Overexpression of GPx4 in insulin-producing RINm5F cells prevents tert-BHP-induced cell death
physiological function
central role of antioxidative enzyme glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death. GPx4 is indispensable for beta-cell function under physiological conditions
physiological function
early brain injury is an essential pathological process after subarachnoid hemorrhage (SAH), with many cell death modalities. Ferroptosis is a regulated cell death caused by the iron-dependent accumulation of lipid peroxidation, which can be prevented by glutathione peroxidase 4 (GPX4), role of GPX4 in neuronal cell death, overview. Among the various mechanisms of early brain injury, lipid peroxidation is an important mechanism and is closely related to a poor clinical outcome. The generation of oxidized phospholipid (oxPL) species plays a crucial role in ferroptosis13. Glutathione peroxidase 4 (GPX4) inhibits ferroptosis by acting as the sole enzyme to convert hydroperoxides into nontoxic lipid alcohols
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). GPX4_RAT
197
0
22225
Swiss-Prot
Secretory Pathway (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
18300
-
recombinant enzyme, glutathione-S-transferase-tag cut off, SDS-PAGE
20000
25900
-
x * 25900, truncated form of nuclear enzyme, lacking the basic nuclear localization signal, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
additional information
-
cytosolic enzyme shows also a minor component in SDS-PAGE at higher molecular weight, which is not further characterized
?
-
x * 25900, truncated form of nuclear enzyme, lacking the basic nuclear localization signal, SDS-PAGE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
replication-deficient human adenovirus containing rat GPX4 cDNA (adenovirus GPX4 [Ad-GPX4]) is used to overexpress GPX4 in rats by injection into the right lateral ventricle of the brain of male Sprague-Dawley rats
additional information
silencing of GPx4 by RNA interference, siRNA-mediated knockdown of GPx4 in insulin-producing beta-cells. Overexpression of GPx4 in insulin-producing RINm5F cells prevents tert-BHP-induced cell death. GPx4 overexpression provides minor protection of insulin-producing RINm5F cells against pro-inflammatory cytokines
additional information
-
(RBL)2H3 cell line stably overexpressing mitochondrial phospholipid hydroperoxide glutathione peroxidase from transfected expression plasmid
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
presence of thiol, e.g. 2-mercaptoethanol, during purification is necessary for stabilization
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate precipitation, DEAE-Sepharose column chromatography, Sephadex G-50 gel filtration, and HiTrap SP column chromatography
-
partially from testis and to homogenity from sperm as recombinant enzyme expressed in Escherichia coli and as wild-type enzyme
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene Gpx4, quantitative real-time PCR expression analysis and absolute quantification of GPx4, recombinant overexpression of hGPx4 in insulin-producing RINm5F cells and in INS-1E cells
expression vector encoding mitochondrial enzyme for overexpression in (RBL)2H3 cell line
-
spermatozoa enzyme, expression in Escherichia coli as glutathione-S-transferase fusion protein
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
PHGPx is useful as a biomarker to screen for detrimental effects of exogenous endocrine disrupting chemicals in testes
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Panfili, E.; Sandri, G.; Ernster, L.
Distribution of glutathione peroxidases and glutathione reductase in rat brain mitochondria
FEBS Lett.
290
35-37
1991
Rattus norvegicus
Maiorino, M.; Gregolin, C.; Ursini, F.
Phospholipid hydroperoxide glutathione peroxidase
Methods Enzymol.
186
448-457
1990
Bos taurus, Canis lupus familiaris, Rattus norvegicus, Sus scrofa
Zhang, L.; Maiorini, M.; Roveri, A.; Ursini, F.
Phospholipid hydroperoxide glutathione peroxidase: specific activity in tissues of rats of different age and comparison with other glutathione peroxidases
Biochim. Biophys. Acta
1006
140-143
1989
Rattus norvegicus
Tramer, F.; Micali, F.; Sandri, G.; Bertoni, A.; Lenzi, A.; Gandini, L.; Panfili, E.
Enzymatic and immunochemical evaluation of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in testes and epididymal spermatozoa of rats of different ages
Int. J. Androl.
25
72-83
2002
Rattus norvegicus
Roveri, A.; Maiorino, M.; Nisii, C.; Ursini, F.
Purification and characterization of phospholipid hydroperoxide glutathione peroxidase from rat testis mitochondrial membranes
Biochim. Biophys. Acta
1208
211-221
1994
Rattus norvegicus
Nomura, K.; Imai, H.; Koumura, T.; Kobayashi, T.; Nakagawa, Y.
Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis
Biochem. J.
351
183-193
2000
Rattus norvegicus
Maiorino, M.; Mauri, P.; Roveri, A.; Benazzi, L.; Toppo, S.; Bosello, V.; Ursini, F.
Primary structure of the nuclear forms of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in rat spermatozoa
FEBS Lett.
579
667-670
2005
Rattus norvegicus
Hattori, H.; Imai, H.; Hanamoto, A.; Furuhama, K.; Nakagawa, Y.
Up-regulation of phospholipid hydroperoxide glutathione peroxidase in rat casein-induced polymorphonuclear neutrophils
Biochem. J.
389
279-287
2005
Rattus norvegicus
Puglisi, R.; Tramer, F.; Carlomagno, G.; Gandini, L.; Panfili, E.; Stefanini, M.; Lenzi, A.; Mangia, F.; Boitani, C.
PHGPx in spermatogenesis: how many functions?
Contraception
72
291-293
2005
Rattus norvegicus
Maiorino, M.; Roveri, A.; Benazzi, L.; Bosello, V.; Mauri, P.; Toppo, S.; Tosatto, S.C.; Ursini, F.
Functional interaction of phospholipid hydroperoxide glutathione peroxidase with sperm mitochondrion-associated cysteine-rich protein discloses the adjacent cysteine motif as a new substrate of the selenoperoxidase
J. Biol. Chem.
280
38395-38402
2005
Rattus norvegicus (P36970)
Conrad, M.; Schneider, M.; Seiler, A.; Bornkamm, G.W.
Physiological role of phospholipid hydroperoxide glutathione peroxidase in mammals
Biol. Chem.
388
1019-1025
2007
Homo sapiens, Mus musculus, Rattus norvegicus, Sus scrofa
Baek, I.J.; Yon, J.M.; Lee, S.R.; Jin, Y.; Kim, M.R.; Ahn, B.; Hong, J.T.; Choo, Y.K.; Lee, B.J.; Yun, Y.W.; Nam, S.Y.
Effects of endocrine disrupting chemicals on expression of phospholipid hydroperoxide glutathione peroxidase mRNA in rat testes
J. Vet. Sci.
8
213-218
2007
Rattus norvegicus
Zafiriou, M.P.; Deva, R.; Ciccoli, R.; Siafaka-Kapadai, A.; Nigam, S.
Biological role of hepoxilins: upregulation of phospholipid hydroperoxide glutathione peroxidase as a cellular response to oxidative stress?
Prostaglandins Leukot. Essent. Fatty Acids
77
209-215
2007
Rattus norvegicus
Kadota, Y.; Suzuki, S.; Ideta, S.; Fukinbara, Y.; Kawakami, T.; Imai, H.; Nakagawa, Y.; Sato, M.
Enhanced metallothionein gene expression induced by mitochondrial oxidative stress is reduced in phospholipid hydroperoxide glutathione peroxidase-overexpressed cells
Eur. J. Pharmacol.
626
166-170
2009
Rattus norvegicus
Kernstock, R.M.; Girotti, A.W.
New strategies for the isolation and activity determination of naturally occurring type-4 glutathione peroxidase
Protein Expr. Purif.
62
216-222
2008
Rattus norvegicus
Kruemmel, B.; Ploetz, T.; Joerns, A.; Lenzen, S.; Mehmeti, I.
The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death
Biochim. Biophys. Acta
1867
166114
2021
Rattus norvegicus (P36970), Rattus norvegicus Lewis-1AR1 (P36970)
Krehelova, A.; Kovarikova, V.; Domorakova, I.; Solar, P.; Pastornicka, A.; Pavliuk-Karachevtseva, A.; Rybarova, S.; Hodorova, I.; Mihalik, J.
Characterization of glutathione peroxidase 4 in rat oocytes, preimplantation embryos, and selected maternal tissues during early development and implantation
Int. J. Mol. Sci.
22
5174
2021
Rattus norvegicus (P36970)
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