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FLASH GENE
Symbol GPX4 contributors: mct/npt/pgu - updated : 24-09-2019
HGNC name glutathione peroxidase 4 (phospholipid hydroperoxidase)
HGNC id 4556
Corresponding disease
HXALI hepoxilin A3 synthase-linked ichthyosis
SMDS spondylometaphyseal dysplasia, Sedaghatian type
Location 19p13.3      Physical location : 1.103.935 - 1.106.786
Synonym name
  • phospholipid hydroperoxidase
  • sperm nucleus glutathione peroxidase
  • hepoxilin A3 (HXA3) synthase
  • phospholipid hydroperoxide glutathione peroxidase,
  • mitochondrial
  • epididymis secretory sperm binding protein
  • Synonym symbol(s) PHGPx, snGPx, HXA3S, MCSP, GPX-4, GSHPx-4, SMDS, snPHGPx
    EC.number 1.11.1.12
    DNA
    TYPE functioning gene
    STRUCTURE 2.79 kb     7 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    7 - 942 - 197 - 2009 19744930
    short form Gpx4 protein is present in somatic tissue mitochondria and is essential for survival and protection against apoptosis in mice
    7 - 964 - 227 - 2009 19744930
    7 - 1031 - 234 - 2009 19744930
    long form Gpx4 protein is important for male fertility in mice
    7 - 788 - 170 - 2009 19744930
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestivesalivary gland   highly
     stomach   highly
    Endocrineparathyroid   highly
    Reproductivemale systemtestis    Homo sapiens
    Visualeyeretina    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Reproductivespermatid Homo sapiens
    Visualrod photoreceptor Homo sapiens
    cell lineage
    cell lines
    fluid/secretion sperm
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
    HOMOLOGY
    interspecies homolog to murine Gpx4
    Homologene
    FAMILY
  • glutathione peroxidase family
  • selenium-dependent glutathione peroxidases family
  • CATEGORY enzyme , transport
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,nucleolus
    intracellular,nuclear envelope
    text
  • at least three isoforms in testis: cytosolic, mitochondrial and nuclear
  • nuclear form of GPX4 has a peculiar distribution in sperm head, being localized to nuclear matrix and acrosome
  • basic FUNCTION
  • glutathione peroxidase, free radical detoxification, catabolic pathway of activated oxygen species, oxydoreductase
  • catalyzing the reduction of hydrogen peroxide, organic hydroperoxide, and lipid peroxides by reduced glutathione and functions in the protection of cells against oxidative damage
  • playing an indispensable role for structural integrity of spermatozoa and to codetermine sperm motility and viability
  • playing a pivotal role in brain development and function
  • multifunctional and it acts as a reducing enzyme of peroxidized phospholipids and thiols and as a structural protein
  • essential antioxidant enzyme having multiple functions
  • GPX5 protein, and the epithelial proteins GPX1, GPX3, and cellular GPX4, all functioning in the mammalian epididymis at different stages of the sperm epididymal journey, and in different epididymis compartments
  • nuclear form of GPX4 is associated with sperm nuclear matrix and is required for proper paternal chromatin decondensation at fertilization
  • GPX4 is a critical antioxidant enzyme for the maturation and survival of photoreceptor cells
  • is essential for maintaining oxidative homeostasis and keeping defense against oxidative stress in conjunctival epithelial cells
  • antioxidant defense enzyme active in repairing oxidative damage to lipids, that is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species
  • ferroptosis inhibition by GPX4 is essential for motor neuron health and survival
  • is an important antioxidant enzyme for maintaining redox status and protecting corneal endothelial cells from oxidative stress
  • is a monomeric glutathione peroxidase, unique in reducing the hydroperoxide group (-OOH) of fatty acids esterified in membrane phospholipids
  • paternal acetylated histones and acrosomal nuclear GPX4 are directly involved in fertilization
  • antioxidant enzyme, having biological important functions such as signaling cell death by suppressing peroxidation of membrane phospholipids
  • GPX4 regulates reactive oxygen species-induced cell death
  • ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4)
  • unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide
  • increased lipid peroxidation resulting from reduced GPX4 expression levels may be causally associated with lung fibrosis development
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS detoxification
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
    fatty acid
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • GRSF1 up-regulates translation of GPX4 mRNA and implicate the two proteins in embryonic brain development
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) HXALI , SMDS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in blood of women with preeclampsia
    constitutional     --low  
    significant reductions in expression of GPX1, GPX3, GPX4 in placentae from women with preeclampsia
    Susceptibility
  • to sterility and infertility
  • to cardiovascular autonomic neuropathy in individuals with type 1 diabetes
  • to Preeclampsia (PE)
  • Variant & Polymorphism other
  • functional variant rs713041 modulates the risk for cardiovascular autonomic neuropathy in individuals with type 1 diabetes
  • rs713041 in GPX4 may play a key role in the pathogenesis of PE
  • Candidate gene
  • is a possible candidate susceptibility gene for Kashin-Beck disease (KBD)
  • Marker
  • GPX4 and GPX7 are possible markers for improving Hepatocellular carcinoma (HCC) diagnosis/prognosis
  • overexpression of GPX4 is an independent prognostic predictor in diffuse large B-cell lymphoma
  • Therapy target
    ANIMAL & CELL MODELS
  • spermatozoa of mice lacking both the sperm nucleus glutathione peroxidase 4 (snGPx4) and the epididymal glutathione peroxidase 5 (GPx5) activities display sperm nucleus structural abnormalities including delayed and defective nuclear compaction, nuclear instability and DNA damage