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Protein

Phospholipid hydroperoxide glutathione peroxidase, mitochondrial

Gene

GPX4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Protects cells against membrane lipid peroxidation and cell death. Required for normal sperm development and male fertility. Could play a major role in protecting mammals from the toxicity of ingested lipid hydroperoxides. Essential for embryonic development. Protects from radiation and oxidative damage (By similarity).By similarity

Catalytic activityi

2 glutathione + a lipid hydroperoxide = glutathione disulfide + lipid + 2 H2O.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei73 – 731

GO - Molecular functioni

  1. glutathione binding Source: Ensembl
  2. glutathione peroxidase activity Source: UniProtKB
  3. phospholipid-hydroperoxide glutathione peroxidase activity Source: UniProtKB-EC
  4. selenium binding Source: Ensembl

GO - Biological processi

  1. aging Source: Ensembl
  2. arachidonic acid metabolic process Source: Reactome
  3. glutathione metabolic process Source: Ensembl
  4. hydrogen peroxide catabolic process Source: Ensembl
  5. lipoxygenase pathway Source: Reactome
  6. multicellular organismal development Source: UniProtKB-KW
  7. oxidation-reduction process Source: UniProtKB
  8. phospholipid metabolic process Source: UniProtKB
  9. regulation of inflammatory response Source: Ensembl
  10. response to estradiol Source: Ensembl
  11. response to oxidative stress Source: InterPro
  12. small molecule metabolic process Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Oxidoreductase, Peroxidase

Enzyme and pathway databases

BioCyciMetaCyc:HS09562-MONOMER.
BRENDAi1.11.1.12. 2681.
ReactomeiREACT_150201. Synthesis of 12-eicosatetraenoic acid derivatives.
REACT_150209. Synthesis of 5-eicosatetraenoic acids.
REACT_150422. Synthesis of 15-eicosatetraenoic acid derivatives.
SABIO-RKP36969.

Protein family/group databases

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

Names & Taxonomyi

Protein namesi
Recommended name:
Phospholipid hydroperoxide glutathione peroxidase, mitochondrial (EC:1.11.1.12)
Short name:
PHGPx
Alternative name(s):
Glutathione peroxidase 4
Short name:
GPx-4
Short name:
GSHPx-4
Gene namesi
Name:GPX4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:4556. GPX4.

Subcellular locationi

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. extracellular vesicular exosome Source: UniProtKB
  3. mitochondrion Source: UniProtKB
  4. nucleus Source: UniProtKB
Complete GO annotation...

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

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi73 – 731U → A: Loss of enzyme activity. 1 Publication
Mutagenesisi73 – 731U → C: Almost complete loss of enzyme activity. 1 Publication

Keywords - Diseasei

Dwarfism

Organism-specific databases

MIMi250220. phenotype.
Orphaneti93317. Spondylometaphyseal dysplasia, Sedaghatian type.
PharmGKBiPA28952.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini? – 197Phospholipid hydroperoxide glutathione peroxidase, mitochondrialPRO_0000013067
Transit peptidei1 – ?MitochondrionSequence Analysis

Proteomic databases

MaxQBiP36969.
PaxDbiP36969.
PRIDEiP36969.

2D gel databases

REPRODUCTION-2DPAGEIPI00304814.
UCD-2DPAGEP36969.

PTM databases

PhosphoSiteiP36969.

Expressioni

Tissue specificityi

Present primarily in testis.

Gene expression databases

BgeeiP36969.
CleanExiHS_GPX4.
ExpressionAtlasiP36969. baseline and differential.
GenevestigatoriP36969.

Organism-specific databases

HPAiCAB008630.

Interactioni

Subunit structurei

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

Protein-protein interaction databases

BioGridi109137. 4 interactions.
IntActiP36969. 3 interactions.
STRINGi9606.ENSP00000346103.

Structurei

Secondary structure

1
197
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi35 – 373Combined sources
Helixi41 – 433Combined sources
Beta strandi45 – 484Combined sources
Beta strandi53 – 553Combined sources
Helixi56 – 594Combined sources
Beta strandi62 – 698Combined sources
Beta strandi71 – 733Combined sources
Helixi76 – 9015Combined sources
Helixi91 – 933Combined sources
Beta strandi95 – 1017Combined sources
Turni104 – 1074Combined sources
Helixi113 – 1219Combined sources
Turni122 – 1243Combined sources
Beta strandi127 – 1304Combined sources
Beta strandi134 – 1374Combined sources
Helixi142 – 1487Combined sources
Turni151 – 1533Combined sources
Beta strandi156 – 1605Combined sources
Beta strandi167 – 1704Combined sources
Beta strandi176 – 1805Combined sources
Helixi187 – 1904Combined sources
Helixi194 – 1963Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2GS3X-ray1.90A36-197[»]
2OBIX-ray1.55A29-197[»]
ProteinModelPortaliP36969.
SMRiP36969. Positions 33-197.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP36969.

Family & Domainsi

Sequence similaritiesi

Belongs to the glutathione peroxidase family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiCOG0386.
GeneTreeiENSGT00760000119230.
HOGENOMiHOG000277054.
HOVERGENiHBG004333.
InParanoidiP36969.
KOiK05361.
OrthoDBiEOG7B5WZH.
PhylomeDBiP36969.
TreeFamiTF338735.

Family and domain databases

Gene3Di3.40.30.10. 1 hit.
InterProiIPR000889. Glutathione_peroxidase.
IPR029759. GPX_AS.
IPR029760. GPX_CS.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERiPTHR11592. PTHR11592. 1 hit.
PfamiPF00255. GSHPx. 1 hit.
[Graphical view]
PIRSFiPIRSF000303. Glutathion_perox. 1 hit.
SUPFAMiSSF52833. SSF52833. 1 hit.
PROSITEiPS00460. GLUTATHIONE_PEROXID_1. 1 hit.
PS00763. GLUTATHIONE_PEROXID_2. 1 hit.
PS51355. GLUTATHIONE_PEROXID_3. 1 hit.
[Graphical view]

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

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

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti2 – 21S → N.2 Publications
Corresponds to variant rs8178967 [ dbSNP | Ensembl ].
VAR_017063
Natural varianti120 – 1201A → T in a patient affected by cryptorchidism. 1 Publication
Corresponds to variant rs76201145 [ dbSNP | Ensembl ].
VAR_017064

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 2727Missing in isoform Cytoplasmic. CuratedVSP_018740Add
BLAST

Non-standard residue

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Non-standard residuei73 – 731Selenocysteine

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.
UCSCiuc021umf.1. human. [P36969-1]

Polymorphism databases

DMDMi172045844.

Keywords - Coding sequence diversityi

Alternative initiation, Polymorphism, Selenocysteine

Cross-referencesi

Web resourcesi

NIEHS-SNPs

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
EntryMethodResolution (Å)ChainPositionsPDBsum
2GS3X-ray1.90A36-197[»]
2OBIX-ray1.55A29-197[»]
ProteinModelPortaliP36969.
SMRiP36969. Positions 33-197.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109137. 4 interactions.
IntActiP36969. 3 interactions.
STRINGi9606.ENSP00000346103.

Chemistry

DrugBankiDB00143. Glutathione.

Protein family/group databases

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

PTM databases

PhosphoSiteiP36969.

Polymorphism databases

DMDMi172045844.

2D gel databases

REPRODUCTION-2DPAGEIPI00304814.
UCD-2DPAGEP36969.

Proteomic databases

MaxQBiP36969.
PaxDbiP36969.
PRIDEiP36969.

Protocols and materials databases

DNASUi2879.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000354171; ENSP00000346103; ENSG00000167468. [P36969-1]
ENST00000611653; ENSP00000483655; ENSG00000167468. [P36969-2]
GeneIDi2879.
KEGGihsa:2879.
UCSCiuc021umf.1. human. [P36969-1]

Organism-specific databases

CTDi2879.
GeneCardsiGC19P001103.
HGNCiHGNC:4556. GPX4.
HPAiCAB008630.
MIMi138322. gene.
250220. phenotype.
neXtProtiNX_P36969.
Orphaneti93317. Spondylometaphyseal dysplasia, Sedaghatian type.
PharmGKBiPA28952.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0386.
GeneTreeiENSGT00760000119230.
HOGENOMiHOG000277054.
HOVERGENiHBG004333.
InParanoidiP36969.
KOiK05361.
OrthoDBiEOG7B5WZH.
PhylomeDBiP36969.
TreeFamiTF338735.

Enzyme and pathway databases

BioCyciMetaCyc:HS09562-MONOMER.
BRENDAi1.11.1.12. 2681.
ReactomeiREACT_150201. Synthesis of 12-eicosatetraenoic acid derivatives.
REACT_150209. Synthesis of 5-eicosatetraenoic acids.
REACT_150422. Synthesis of 15-eicosatetraenoic acid derivatives.
SABIO-RKP36969.

Miscellaneous databases

ChiTaRSiGPX4. human.
EvolutionaryTraceiP36969.
GeneWikiiGPX4.
GenomeRNAii2879.
NextBioi11367.
PROiP36969.
SOURCEiSearch...

Gene expression databases

BgeeiP36969.
CleanExiHS_GPX4.
ExpressionAtlasiP36969. baseline and differential.
GenevestigatoriP36969.

Family and domain databases

Gene3Di3.40.30.10. 1 hit.
InterProiIPR000889. Glutathione_peroxidase.
IPR029759. GPX_AS.
IPR029760. GPX_CS.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERiPTHR11592. PTHR11592. 1 hit.
PfamiPF00255. GSHPx. 1 hit.
[Graphical view]
PIRSFiPIRSF000303. Glutathion_perox. 1 hit.
SUPFAMiSSF52833. SSF52833. 1 hit.
PROSITEiPS00460. GLUTATHIONE_PEROXID_1. 1 hit.
PS00763. GLUTATHIONE_PEROXID_2. 1 hit.
PS51355. GLUTATHIONE_PEROXID_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase."
    Esworthy R.S., Doan K., Doroshow J.H., Chu F.-F.
    Gene 144:317-318(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Testis.
  2. "Structural organization of the human selenium-dependent phospholipid hydroperoxide glutathione peroxidase gene (GPX4): chromosomal localization to 19p13.3."
    Kelner M.J., Montoya M.A.
    Biochem. Biophys. Res. Commun. 249:53-55(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  3. NIEHS SNPs program
    Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ASN-2.
  4. "The DNA sequence and biology of human chromosome 19."
    Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V.
    , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
    Nature 428:529-535(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Brain, Eye, Lung, Pancreas and Testis.
  6. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  7. "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
    Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., Ye M., Zou H.
    J. Proteomics 96:253-262(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  8. "Structural basis for catalytic activity and enzyme polymerization of phospholipid hydroperoxide glutathione peroxidase-4 (GPx4)."
    Scheerer P., Borchert A., Krauss N., Wessner H., Gerth C., Hoehne W., Kuhn H.
    Biochemistry 46:9041-9049(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 29-197 (ISOFORM CYTOPLASMIC), SUBUNIT, MUTAGENESIS OF SEC-73.
  9. "Crystal structure of the selenocysteine to glycine mutant of human glutathione peroxidase 4 (GPX4)."
    Structural genomics consortium (SGC)
    Submitted (JAN-2009) to the PDB data bank
    Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 36-197.
  10. Cited for: VARIANTS ASN-2 AND THR-120.
  11. Cited for: INVOLVEMENT IN SMDS.

Entry informationi

Entry nameiGPX4_HUMAN
AccessioniPrimary (citable) accession number: P36969
Secondary accession number(s): O43381, Q6PJ59, Q9UPK2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: February 26, 2008
Last modified: April 1, 2015
This is version 160 of the entry and version 3 of the sequence. [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. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.