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Protein

Phospholipid hydroperoxide glutathione peroxidase

Gene

GPX4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (By similarity). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (PubMed:24439385). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (By similarity).By similarity1 Publication

Catalytic activityi

2 glutathione + a hydroperoxy-fatty-acyl-[lipid] = glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei73By similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, Oxidoreductase, Peroxidase

Enzyme and pathway databases

BioCyciMetaCyc:HS09562-MONOMER
BRENDAi1.11.1.12 2681
ReactomeiR-HSA-2142688 Synthesis of 5-eicosatetraenoic acids
R-HSA-2142712 Synthesis of 12-eicosatetraenoic acid derivatives
R-HSA-2142770 Synthesis of 15-eicosatetraenoic acid derivatives
R-HSA-9018676 Biosynthesis of D-series resolvins
R-HSA-9018896 Biosynthesis of E-series 18(S)-resolvins
R-HSA-9020265 Biosynthesis of aspirin-triggered D-series resolvins
R-HSA-9023661 Biosynthesis of E-series 18(R)-resolvins
SABIO-RKiP36969

Protein family/group databases

MoonProtiP36969
PeroxiBasei3603 HsGPx04-A
3632 HsGPx04-B
3633 HsGPx04-C

Chemistry databases

SwissLipidsiSLP:000001633

Names & Taxonomyi

Protein namesi
Recommended name:
Phospholipid hydroperoxide glutathione peroxidase (EC:1.11.1.12)
Short name:
PHGPx
Alternative name(s):
Glutathione peroxidase 41 Publication
Short name:
GPx-41 Publication
Short name:
GSHPx-41 Publication
Gene namesi
Name:GPX41 PublicationImported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000167468.16
HGNCiHGNC:4556 GPX4
MIMi138322 gene
neXtProtiNX_P36969

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Spondylometaphyseal dysplasia, Sedaghatian type (SMDS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDS is a neonatal lethal form characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities.
See also OMIM:250220
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_08014090 – 197Missing in SMDS. 1 PublicationAdd BLAST108

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi73U → A: Loss of enzyme activity. 1 Publication1
Mutagenesisi73U → C: Almost complete loss of enzyme activity. 1 Publication1

Keywords - Diseasei

Dwarfism

Organism-specific databases

DisGeNETi2879
MalaCardsiGPX4
MIMi250220 phenotype
OpenTargetsiENSG00000167468
Orphaneti93317 Spondylometaphyseal dysplasia, Sedaghatian type
PharmGKBiPA28952

Chemistry databases

DrugBankiDB00143 Glutathione

Polymorphism and mutation databases

BioMutaiGPX4
DMDMi172045844

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_0000013067? – 197Phospholipid hydroperoxide glutathione peroxidase
Transit peptidei1 – ?MitochondrionSequence analysis

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei40PhosphoserineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP36969
MaxQBiP36969
PaxDbiP36969
PeptideAtlasiP36969
PRIDEiP36969
ProteomicsDBi55250
55251 [P36969-2]

2D gel databases

REPRODUCTION-2DPAGEiIPI00304814
UCD-2DPAGEiP36969

PTM databases

iPTMnetiP36969
PhosphoSitePlusiP36969
SwissPalmiP36969

Expressioni

Tissue specificityi

Present primarily in testis.1 Publication

Gene expression databases

BgeeiENSG00000167468 Expressed in 230 organ(s), highest expression level in right testis
CleanExiHS_GPX4
ExpressionAtlasiP36969 baseline and differential
GenevisibleiP36969 HS

Organism-specific databases

HPAiCAB008630
HPA047224
HPA058546

Interactioni

Subunit structurei

Monomer. Has a tendency to form higher mass oligomers.1 Publication

GO - Molecular functioni

Protein-protein interaction databases

BioGridi109137, 41 interactors
DIPiDIP-53543N
IntActiP36969, 8 interactors
MINTiP36969
STRINGi9606.ENSP00000346103

Structurei

Secondary structure

1197
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP36969
SMRiP36969
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP36969

Family & Domainsi

Sequence similaritiesi

Belongs to the glutathione peroxidase family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG1651 Eukaryota
COG0386 LUCA
GeneTreeiENSGT00760000119230
HOGENOMiHOG000277054
HOVERGENiHBG004333
InParanoidiP36969
KOiK05361
OMAiGTDESIH
PhylomeDBiP36969
TreeFamiTF338735

Family and domain databases

CDDicd00340 GSH_Peroxidase, 1 hit
InterProiView protein in InterPro
IPR000889 Glutathione_peroxidase
IPR029759 GPX_AS
IPR029760 GPX_CS
IPR036249 Thioredoxin-like_sf
PANTHERiPTHR11592 PTHR11592, 1 hit
PfamiView protein in Pfam
PF00255 GSHPx, 1 hit
PIRSFiPIRSF000303 Glutathion_perox, 1 hit
SUPFAMiSSF52833 SSF52833, 1 hit
PROSITEiView protein in PROSITE
PS00460 GLUTATHIONE_PEROXID_1, 1 hit
PS00763 GLUTATHIONE_PEROXID_2, 1 hit
PS51355 GLUTATHIONE_PEROXID_3, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

This entry has 2 described isoforms and 9 potential isoforms that are computationally mapped.Show allAlign All

Isoform Mitochondrial (identifier: P36969-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MSLGRLCRLL KPALLCGALA APGLAGTMCA SRDDWRCARS MHEFSAKDID
60 70 80 90 100
GHMVNLDKYR GFVCIVTNVA SQUGKTEVNY TQLVDLHARY AECGLRILAF
110 120 130 140 150
PCNQFGKQEP GSNEEIKEFA AGYNVKFDMF SKICVNGDDA HPLWKWMKIQ
160 170 180 190
PKGKGILGNA IKWNFTKFLI DKNGCVVKRY GPMEEPLVIE KDLPHYF
Length:197
Mass (Da):22,175
Last modified:February 26, 2008 - v3
Checksum:i1AE3BC7AE42FDDB1
GO
Isoform Cytoplasmic (identifier: P36969-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-27: Missing.

Show »
Length:170
Mass (Da):19,525
Checksum:iB7FA0B3831DEF7DB
GO

Computationally mapped potential isoform sequencesi

There are 9 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
K7ENB4K7ENB4_HUMAN
Glutathione peroxidase
GPX4
180Annotation score:
A0A087X2I2A0A087X2I2_HUMAN
Glutathione peroxidase
GPX4
196Annotation score:
R4GNE4R4GNE4_HUMAN
Glutathione peroxidase
GPX4
179Annotation score:
K7EKX7K7EKX7_HUMAN
Glutathione peroxidase
GPX4
175Annotation score:
K7EJ20K7EJ20_HUMAN
Glutathione peroxidase
GPX4
242Annotation score:
A0A087WT12A0A087WT12_HUMAN
Glutathione peroxidase
GPX4
233Annotation score:
A0A087X247A0A087X247_HUMAN
Phospholipid hydroperoxide glutathi...
GPX4
134Annotation score:
K7ERP4K7ERP4_HUMAN
Glutathione peroxidase
GPX4
155Annotation score:
A0A0A0MTT1A0A0A0MTT1_HUMAN
Glutathione peroxidase
GPX4
166Annotation score:

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0170632S → N2 PublicationsCorresponds to variant dbSNP:rs8178967Ensembl.1
Natural variantiVAR_08014090 – 197Missing in SMDS. 1 PublicationAdd BLAST108
Natural variantiVAR_017064120A → T in a patient affected by cryptorchidism. 1 PublicationCorresponds to variant dbSNP:rs76201145Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0187401 – 27Missing in isoform Cytoplasmic. CuratedAdd BLAST27

Non-standard residue

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Non-standard residuei73Selenocysteine2 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X71973 mRNA Translation: CAA50793.1
AF060972 Genomic DNA Translation: AAC32261.1
AY324108 Genomic DNA Translation: AAP72965.1
AC004151 Genomic DNA Translation: AAC03239.1
AC005390 Genomic DNA Translation: AAC28920.1
BC011836 mRNA Translation: AAH11836.1
BC021567 mRNA Translation: AAH21567.1
BC022071 mRNA Translation: AAH22071.1
BC032695 mRNA Translation: AAH32695.3
BC039849 mRNA Translation: AAH39849.1
CCDSiCCDS42457.1 [P36969-1]
PIRiT02747
RefSeqiNP_001034936.1, NM_001039847.2
NP_002076.2, NM_002085.4 [P36969-1]
UniGeneiHs.433951

Genome annotation databases

EnsembliENST00000354171; ENSP00000346103; ENSG00000167468 [P36969-1]
ENST00000611653; ENSP00000483655; ENSG00000167468 [P36969-2]
GeneIDi2879
KEGGihsa:2879
UCSCiuc021umg.3 human [P36969-1]

Keywords - Coding sequence diversityi

Alternative initiation, Polymorphism, Selenocysteine

Similar proteinsi

Cross-referencesi

Web resourcesi

NIEHS-SNPs
Protein Spotlight

Life, a subtle balance - Issue 205 of July 2018

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X71973 mRNA Translation: CAA50793.1
AF060972 Genomic DNA Translation: AAC32261.1
AY324108 Genomic DNA Translation: AAP72965.1
AC004151 Genomic DNA Translation: AAC03239.1
AC005390 Genomic DNA Translation: AAC28920.1
BC011836 mRNA Translation: AAH11836.1
BC021567 mRNA Translation: AAH21567.1
BC022071 mRNA Translation: AAH22071.1
BC032695 mRNA Translation: AAH32695.3
BC039849 mRNA Translation: AAH39849.1
CCDSiCCDS42457.1 [P36969-1]
PIRiT02747
RefSeqiNP_001034936.1, NM_001039847.2
NP_002076.2, NM_002085.4 [P36969-1]
UniGeneiHs.433951

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2GS3X-ray1.90A36-197[»]
2OBIX-ray1.55A29-197[»]
5H5QX-ray1.10A29-197[»]
5H5RX-ray1.20A29-197[»]
5H5SX-ray1.85A29-197[»]
6ELWX-ray1.30A29-197[»]
ProteinModelPortaliP36969
SMRiP36969
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109137, 41 interactors
DIPiDIP-53543N
IntActiP36969, 8 interactors
MINTiP36969
STRINGi9606.ENSP00000346103

Chemistry databases

DrugBankiDB00143 Glutathione
SwissLipidsiSLP:000001633

Protein family/group databases

MoonProtiP36969
PeroxiBasei3603 HsGPx04-A
3632 HsGPx04-B
3633 HsGPx04-C

PTM databases

iPTMnetiP36969
PhosphoSitePlusiP36969
SwissPalmiP36969

Polymorphism and mutation databases

BioMutaiGPX4
DMDMi172045844

2D gel databases

REPRODUCTION-2DPAGEiIPI00304814
UCD-2DPAGEiP36969

Proteomic databases

EPDiP36969
MaxQBiP36969
PaxDbiP36969
PeptideAtlasiP36969
PRIDEiP36969
ProteomicsDBi55250
55251 [P36969-2]

Protocols and materials databases

DNASUi2879
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000354171; ENSP00000346103; ENSG00000167468 [P36969-1]
ENST00000611653; ENSP00000483655; ENSG00000167468 [P36969-2]
GeneIDi2879
KEGGihsa:2879
UCSCiuc021umg.3 human [P36969-1]

Organism-specific databases

CTDi2879
DisGeNETi2879
EuPathDBiHostDB:ENSG00000167468.16
GeneCardsiGPX4
HGNCiHGNC:4556 GPX4
HPAiCAB008630
HPA047224
HPA058546
MalaCardsiGPX4
MIMi138322 gene
250220 phenotype
neXtProtiNX_P36969
OpenTargetsiENSG00000167468
Orphaneti93317 Spondylometaphyseal dysplasia, Sedaghatian type
PharmGKBiPA28952
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1651 Eukaryota
COG0386 LUCA
GeneTreeiENSGT00760000119230
HOGENOMiHOG000277054
HOVERGENiHBG004333
InParanoidiP36969
KOiK05361
OMAiGTDESIH
PhylomeDBiP36969
TreeFamiTF338735

Enzyme and pathway databases

BioCyciMetaCyc:HS09562-MONOMER
BRENDAi1.11.1.12 2681
ReactomeiR-HSA-2142688 Synthesis of 5-eicosatetraenoic acids
R-HSA-2142712 Synthesis of 12-eicosatetraenoic acid derivatives
R-HSA-2142770 Synthesis of 15-eicosatetraenoic acid derivatives
R-HSA-9018676 Biosynthesis of D-series resolvins
R-HSA-9018896 Biosynthesis of E-series 18(S)-resolvins
R-HSA-9020265 Biosynthesis of aspirin-triggered D-series resolvins
R-HSA-9023661 Biosynthesis of E-series 18(R)-resolvins
SABIO-RKiP36969

Miscellaneous databases

ChiTaRSiGPX4 human
EvolutionaryTraceiP36969
GeneWikiiGPX4
GenomeRNAii2879
PROiPR:P36969
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000167468 Expressed in 230 organ(s), highest expression level in right testis
CleanExiHS_GPX4
ExpressionAtlasiP36969 baseline and differential
GenevisibleiP36969 HS

Family and domain databases

CDDicd00340 GSH_Peroxidase, 1 hit
InterProiView protein in InterPro
IPR000889 Glutathione_peroxidase
IPR029759 GPX_AS
IPR029760 GPX_CS
IPR036249 Thioredoxin-like_sf
PANTHERiPTHR11592 PTHR11592, 1 hit
PfamiView protein in Pfam
PF00255 GSHPx, 1 hit
PIRSFiPIRSF000303 Glutathion_perox, 1 hit
SUPFAMiSSF52833 SSF52833, 1 hit
PROSITEiView protein in PROSITE
PS00460 GLUTATHIONE_PEROXID_1, 1 hit
PS00763 GLUTATHIONE_PEROXID_2, 1 hit
PS51355 GLUTATHIONE_PEROXID_3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiGPX4_HUMAN
AccessioniPrimary (citable) accession number: P36969
Secondary accession number(s): O43381, Q6PJ59, Q9UPK2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: February 26, 2008
Last modified: October 10, 2018
This is version 192 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  4. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  5. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  6. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  7. Protein Spotlight
    Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
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Main funding by: National Institutes of Health

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