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P36969 (GPX4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 153. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Phospholipid hydroperoxide glutathione peroxidase, mitochondrial

Short name=PHGPx
EC=1.11.1.12
Alternative name(s):
Glutathione peroxidase 4
Short name=GPx-4
Short name=GSHPx-4
Gene names
Name:GPX4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length197 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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.

Catalytic activity

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

Subunit structure

Monomer. Has a tendency to form higher mass oligomers. Ref.7

Subcellular location

Isoform Mitochondrial: Mitochondrion.

Isoform Cytoplasmic: Cytoplasm.

Tissue specificity

Present primarily in testis.

Sequence similarities

Belongs to the glutathione peroxidase family.

Ontologies

Keywords
   Cellular componentCytoplasm
Mitochondrion
   Coding sequence diversityAlternative initiation
Polymorphism
Selenocysteine
   DomainTransit peptide
   Molecular functionDevelopmental protein
Oxidoreductase
Peroxidase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaging

Inferred from electronic annotation. Source: Ensembl

arachidonic acid metabolic process

Traceable author statement. Source: Reactome

chromatin organization

Inferred from electronic annotation. Source: Ensembl

glutathione metabolic process

Inferred from electronic annotation. Source: Ensembl

hydrogen peroxide catabolic process

Inferred from electronic annotation. Source: Ensembl

lipoxygenase pathway

Traceable author statement. Source: Reactome

multicellular organismal development

Inferred from electronic annotation. Source: UniProtKB-KW

oxidation-reduction process

Traceable author statement Ref.2. Source: UniProtKB

phospholipid metabolic process

Traceable author statement Ref.1. Source: UniProtKB

regulation of inflammatory response

Inferred from electronic annotation. Source: Ensembl

response to estradiol

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

spermatogenesis

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

extracellular vesicular exosome

Inferred from direct assay PubMed 19056867PubMed 23376485. Source: UniProt

mitochondrial inner membrane

Inferred from electronic annotation. Source: Ensembl

mitochondrion

Traceable author statement Ref.2. Source: UniProtKB

nuclear envelope

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from direct assay PubMed 21630459. Source: UniProt

   Molecular_functionglutathione binding

Inferred from electronic annotation. Source: Ensembl

glutathione peroxidase activity

Traceable author statement Ref.2. Source: UniProtKB

phospholipid-hydroperoxide glutathione peroxidase activity

Inferred from electronic annotation. Source: UniProtKB-EC

selenium binding

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative initiation. [Align] [Select]
Isoform Mitochondrial (identifier: P36969-1)

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.
Isoform Cytoplasmic (identifier: P36969-2)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – ?Mitochondrion Potential
Chain? – 197Phospholipid hydroperoxide glutathione peroxidase, mitochondrialPRO_0000013067

Sites

Active site731

Amino acid modifications

Non-standard residue731Selenocysteine

Natural variations

Alternative sequence1 – 2727Missing in isoform Cytoplasmic.
VSP_018740
Natural variant21S → N. Ref.3 Ref.9
Corresponds to variant rs8178967 [ dbSNP | Ensembl ].
VAR_017063
Natural variant1201A → T in a patient affected by cryptorchidism. Ref.9
Corresponds to variant rs76201145 [ dbSNP | Ensembl ].
VAR_017064

Experimental info

Mutagenesis731U → A: Loss of enzyme activity. Ref.7
Mutagenesis731U → C: Almost complete loss of enzyme activity. Ref.7

Secondary structure

.......................................... 197
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform Mitochondrial [UniParc].

Last modified February 26, 2008. Version 3.
Checksum: 1AE3BC7AE42FDDB1

FASTA19722,175
        10         20         30         40         50         60 
MSLGRLCRLL KPALLCGALA APGLAGTMCA SRDDWRCARS MHEFSAKDID GHMVNLDKYR 

        70         80         90        100        110        120 
GFVCIVTNVA SQUGKTEVNY TQLVDLHARY AECGLRILAF PCNQFGKQEP GSNEEIKEFA 

       130        140        150        160        170        180 
AGYNVKFDMF SKICVNGDDA HPLWKWMKIQ PKGKGILGNA IKWNFTKFLI DKNGCVVKRY 

       190 
GPMEEPLVIE KDLPHYF 

« Hide

Isoform Cytoplasmic [UniParc].

Checksum: B7FA0B3831DEF7DB
Show »

FASTA17019,525

References

« Hide 'large scale' references
[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(1994) [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(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]NIEHS SNPs program
Submitted (JUN-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. expand/collapse author list , 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(2004) [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(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain, Eye, Lung, Pancreas and Testis.
[6]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]"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(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 29-197 (ISOFORM CYTOPLASMIC), SUBUNIT, MUTAGENESIS OF SEC-73.
[8]"Crystal structure of the selenocysteine to glycine mutant of human glutathione peroxidase 4 (GPX4)."
Structural genomics consortium (SGC)
Submitted (FEB-2009) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 36-197.
[9]"Genetic variations of gpx-4 and male infertility in humans."
Maiorino M., Bosello V., Ursini F., Foresta C., Garolla A., Scapin M., Sztajer H., Flohe L.
Biol. Reprod. 68:1134-1141(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS ASN-2 AND THR-120.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS42457.1. [P36969-1]
PIRT02747.
RefSeqNP_001034936.1. NM_001039847.2.
NP_002076.2. NM_002085.4. [P36969-1]
UniGeneHs.433951.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2GS3X-ray1.90A36-197[»]
2OBIX-ray1.55A29-197[»]
ProteinModelPortalP36969.
SMRP36969. Positions 33-197.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109137. 4 interactions.
IntActP36969. 3 interactions.
STRING9606.ENSP00000346103.

Chemistry

DrugBankDB00143. Glutathione.

Protein family/group databases

PeroxiBase3603. HsGPx04-A.
3632. HsGPx04-B.
3633. HsGPx04-C.

PTM databases

PhosphoSiteP36969.

Polymorphism databases

DMDM172045844.

2D gel databases

REPRODUCTION-2DPAGEIPI00304814.
UCD-2DPAGEP36969.

Proteomic databases

MaxQBP36969.
PaxDbP36969.
PRIDEP36969.

Protocols and materials databases

DNASU2879.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000354171; ENSP00000346103; ENSG00000167468. [P36969-1]
GeneID2879.
KEGGhsa:2879.
UCSCuc021umf.1. human. [P36969-1]

Organism-specific databases

CTD2879.
GeneCardsGC19P001103.
HGNCHGNC:4556. GPX4.
HPACAB008630.
MIM138322. gene.
neXtProtNX_P36969.
PharmGKBPA28952.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0386.
HOGENOMHOG000277054.
HOVERGENHBG004333.
InParanoidP36969.
KOK05361.
OrthoDBEOG7B5WZH.
PhylomeDBP36969.
TreeFamTF338735.

Enzyme and pathway databases

BioCycMetaCyc:HS09562-MONOMER.
ReactomeREACT_111217. Metabolism.
SABIO-RKP36969.

Gene expression databases

ArrayExpressP36969.
BgeeP36969.
CleanExHS_GPX4.
GenevestigatorP36969.

Family and domain databases

Gene3D3.40.30.10. 1 hit.
InterProIPR000889. Glutathione_peroxidase.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERPTHR11592. PTHR11592. 1 hit.
PfamPF00255. GSHPx. 1 hit.
[Graphical view]
PIRSFPIRSF000303. Glutathion_perox. 1 hit.
SUPFAMSSF52833. SSF52833. 1 hit.
PROSITEPS00460. GLUTATHIONE_PEROXID_1. 1 hit.
PS00763. GLUTATHIONE_PEROXID_2. 1 hit.
PS51355. GLUTATHIONE_PEROXID_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSGPX4. human.
EvolutionaryTraceP36969.
GeneWikiGPX4.
GenomeRNAi2879.
NextBio11367.
PROP36969.
SOURCESearch...

Entry information

Entry nameGPX4_HUMAN
AccessionPrimary (citable) accession number: P36969
Secondary accession number(s): O43381, Q6PJ59, Q9UPK2
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: February 26, 2008
Last modified: July 9, 2014
This is version 153 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 19

Human chromosome 19: entries, gene names and cross-references to MIM