Reviewed, UniProtKB/Swiss-Prot P36969 (GPX4_HUMAN)

Names and origin

Protein names

Recommended name:
    Phospholipid hydroperoxide glutathione peroxidase, mitochondrial
      Short name=PHGPx
    EC=1.11.1.12
Alternative name(s):
    GPX-4

Gene names

Name:

GPX4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	197 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.
Subcellular location	Mitochondrion. Cytoplasm.
Tissue specificity	Present primarily in testis.
Involvement in disease	Defects in GPX4 may be a cause of infertility.
Sequence similarities	Belongs to the glutathione peroxidase family.

Ontologies

Keywords
Cellular component	Cytoplasm Mitochondrion
Coding sequence diversity	Alternative initiation Polymorphism Selenocysteine
Disease	Disease mutation
Domain	Transit peptide
Ligand	Selenium
Molecular function	Developmental protein Oxidoreductase Peroxidase
Technical term	3D-structure
Gene Ontology (GO)
Biological process	multicellular organismal development Inferred from electronic annotation. Source: UniProtKB-KW oxidation reduction Ref.2 Traceable author statement. Source: UniProtKB phospholipid metabolic process Ref.1 Traceable author statement. Source: UniProtKB
Molecular function	glutathione peroxidase activity Ref.2 Traceable author statement. Source: UniProtKB phospholipid-hydroperoxide glutathione peroxidase activity Inferred from electronic annotation. Source: EC selenium binding Inferred from electronic annotation. Source: UniProtKB-KW
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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – ?

Mitochondrion Potential

Chain

? – 197

Phospholipid hydroperoxide glutathione peroxidase, mitochondrial

PRO_0000013067

Sites

Active site

73

1

Amino acid modifications

Non-standard residue

73

1

Selenocysteine

Natural variations

Alternative sequence

1 – 27

27

Missing in isoform Cytoplasmic.

VSP_018740

Natural variant

2

1

S → N: dbSNP rs8178967. Ref.3 Ref.9

VAR_017063

Natural variant

120

1

A → T in infertility; reduced activity. Ref.9

VAR_017064

Experimental info

Mutagenesis

73

1

U → A: Loss of enzyme activity.

Mutagenesis

73

1

U → C: Almost complete loss of enzyme activity.

Secondary structure

1

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197

Helix Strand Turn

Details...

Helix

41 – 43

3

Beta strand

44 – 48

5

Beta strand

53 – 55

3

Helix

56 – 59

4

Beta strand

62 – 69

8

Beta strand

71 – 73

3

Helix

76 – 90

15

Helix

91 – 93

3

Beta strand

95 – 101

7

Turn

104 – 107

4

Helix

113 – 122

10

Beta strand

127 – 130

4

Beta strand

134 – 137

4

Helix

142 – 147

6

Helix

151 – 153

3

Beta strand

156 – 160

5

Beta strand

167 – 170

4

Beta strand

176 – 180

5

Helix

186 – 192

7

Helix

193 – 196

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform Mitochondrial [UniParc]. Last modified February 26, 2008. Version 3. Checksum: 1AE3BC7AE42FDDB1	FASTA	197	22,175
	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
	Isoform Cytoplasmic. Checksum: B7FA0B3831DEF7DB	FASTA	170	19,525
	10 20 30 40 50 60 MCASRDDWRC ARSMHEFSAK DIDGHMVNLD KYRGFVCIVT NVASQUGKTE VNYTQLVDLH 70 80 90 100 110 120 ARYAECGLRI LAFPCNQFGK QEPGSNEEIK EFAAGYNVKF DMFSKICVNG DDAHPLWKWM 130 140 150 160 170 KIQPKGKGIL GNAIKWNFTK FLIDKNGCVV KRYGPMEEPL VIEKDLPHYF

References

	« Hide 'large scale' referencesShow '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: 8039723] [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: 9705830] [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. , 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: 15057824] [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain, Eye, Lung, Pancreas and Testis.
[6]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[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: 17630701] [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: 12606444] [Abstract] Cited for: VARIANT INFERTILITY THR-120, VARIANT ASN-2.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.

IPI

IPI00304814.
IPI00745335.

PIR

T02747.

RefSeq

NP_001034936.1.
NP_001034937.1.
NP_002076.2.

UniGene

Hs.433951

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2GS3	X-ray	1.90	A	36-197	[»]
2OBI	X-ray	1.55	A	29-197	[»]

ModBase

Search...

Protein family/group databases

PeroxiBase

3603. HsGPx04-a.
3632. HsGPx04-b.
3633. HsGPx04-c.

2-D gel databases

REPRODUCTION-2DPAGE

IPI00304814.

Proteomic databases

PRIDE

P36969.

Genome annotation databases

Ensembl

ENSG00000167468. Homo sapiens. [Contig view]

GeneID

2879.

KEGG

hsa:2879.

Organism-specific databases

GeneCards

GC19P001054.

HGNC

HGNC:4556. GPX4.

HPA

CAB008630.

MIM

138322. gene.

PharmGKB

PA28952.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P36969.

HOVERGEN

P36969.

OMA

P36969. AQNGNDL.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-9881.

BRENDA

1.11.1.12. 247.

Gene expression databases

Bgee

P36969.

CleanEx

HS_GPX4.

GermOnline

ENSG00000167468. Homo sapiens.

Family and domain databases

InterPro

IPR000889. Glutathione_peroxidase.
IPR012335. Thioredoxin_fold.
[Graphical view]

Gene3D

G3DSA:3.40.30.10. Thioredoxin_fold. 1 hit.

PANTHER

PTHR11592. Glut_peroxidase. 1 hit.

Pfam

PF00255. GSHPx. 1 hit.
[Graphical view]

PIRSF

PIRSF000303. Glutathion_perox. 1 hit.

PROSITE

PS00460. GLUTATHIONE_PEROXID_1. 1 hit.
PS00763. GLUTATHIONE_PEROXID_2. 1 hit.
PS51355. GLUTATHIONE_PEROXID_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00143. Glutathione.

NextBio

11367.

SOURCE

Search...

Entry information

Entry name

GPX4_HUMAN

Accession

Primary (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:	June 16, 2009
This is version 97 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)