GPX4 (Glutathione Peroxidase 4, also known as PHGPx) is a monomeric selenoprotein glutathione peroxidase containing an active-site selenocysteine (Sec46). It uniquely reduces phospholipid hydroperoxides (PLOOHs) directly within membranes to their corresponding alcohols using reduced glutathione (GSH) as the electron donor. GPX4 is the central enzymatic suppressor of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. Three isoforms exist from alternative promoters: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct subcellular functions including protection of membrane lipids, mitochondrial integrity, and sperm chromatin stability during spermatogenesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0034599 cellular response to oxidative stress | IBA GO_REF:0000033 | ACCEPT | Summary: GPX4 is a key antioxidant enzyme that protects cells from oxidative damage by reducing lipid hydroperoxides. The deep research confirms GPX4 plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (GPX4-deep-research-falcon.md). This annotation is appropriate as a broader process encompassing GPX4's core protective function. Reason: GPX4's primary role is to detoxify lipid hydroperoxides, which is a central response to oxidative stress. The IBA annotation is well-supported by phylogenetic evidence and consistent with GPX4's function across orthologs. Supporting Evidence: PMID:11115402 the increase in hydroperoxide tone (a situation found under oxidative stress or selenium deficiency or on incubation with 12-HPETE) partly diverts the 12-lipoxygenase pathway from the reduction route to the isomerization route |
| GO:0019372 lipoxygenase pathway | IBA GO_REF:0000033 | ACCEPT | Summary: GPX4 reduces hydroperoxy products of the 12-lipoxygenase pathway, thereby regulating the flux through this pathway. PMID:11115402 demonstrated that both GPx-1 and PHGPx are involved in the regulatory network of the 12-lipoxygenase pathway. Reason: GPX4's role in the lipoxygenase pathway is experimentally documented. The enzyme reduces 12-HpETE to 12-HETE, modulating the balance between reduction and isomerization routes. This represents a core function of GPX4 in arachidonic acid metabolism. Supporting Evidence: PMID:11115402 We therefore believe that both GPx-1 and PHGPx are involved in the regulatory network of the 12-lipoxygenase pathway in platelets and other mammalian cells |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: The mitochondrial isoform (mGPX4) localizes to mitochondria via an N-terminal targeting sequence. The deep research indicates mGPX4 targets mitochondria and preserves mitochondrial membrane integrity (GPX4-deep-research-falcon.md). Reason: Mitochondrial localization is well-established for the mGPX4 isoform. This annotation appropriately captures one of the three documented subcellular localizations of GPX4 isoforms. Supporting Evidence: file:human/GPX4/GPX4-deep-research-falcon.md mGPX4 targets mitochondria and preserves mitochondrial membrane integrity |
| GO:0004602 glutathione peroxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: GPX4 is a member of the glutathione peroxidase family and exhibits glutathione peroxidase activity. PMID:36608588 directly demonstrated GPX4 reduces H2O2 and other soluble hydroperoxides using glutathione, though with lower efficiency than GPX1 for simple substrates. Reason: While GPX4's more specific function is phospholipid-hydroperoxide glutathione peroxidase activity (GO:0047066), general glutathione peroxidase activity is also correct. Both annotations should be retained. GPX4 can reduce H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide. Supporting Evidence: PMID:36608588 small soluble hydroperoxides such as H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide were reduced by all three isoforms PMID:17630701 Multiple mutations of the catalytic triad indicated its functional importance |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: The nuclear isoform (nGPX4) localizes to the nucleus, particularly during spermatogenesis where it contributes to chromatin stability. Deep research confirms nGPX4 localizes to nuclei during spermatogenesis. Reason: Nuclear localization is documented for nGPX4, which has a specialized role in sperm development. Proteomic characterization of human sperm nucleus (PMID:21630459) supports this localization. Supporting Evidence: PMID:21630459 Generating a catalogue of sperm nuclear proteins is an important first step towards the clarification of the function of the paternal chromatin transmitted to the oocyte upon fertilization |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the core molecular function of GPX4. The enzyme uniquely reduces phospholipid hydroperoxides directly within membranes. PMID:36608588 confirmed GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide. Reason: This is GPX4's defining enzymatic activity and represents the most specific MF annotation. This is strongly supported by multiple experimental studies and represents the primary molecular function of the protein. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0004601 peroxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: GPX4 possesses peroxidase activity, reducing various hydroperoxides. This is a parent term of the more specific glutathione peroxidase activity. Reason: This is a valid broader annotation. GPX4 is indeed a peroxidase, and this IEA annotation based on InterPro domain (IPR000889) is appropriate. More specific terms are also annotated. Supporting Evidence: PMID:36608588 The GPXs are important for reducing hydroperoxides in a glutathione-consuming manner and thus regulate cellular redox homeostasis |
| GO:0004602 glutathione peroxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation for glutathione peroxidase activity. This IEA annotation is based on orthology to mouse GPX4. Reason: Valid annotation derived from orthology evidence. The underlying activity is well-supported experimentally. Supporting Evidence: PMID:36608588 small soluble hydroperoxides such as H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide were reduced by all three isoforms |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The cytoplasmic isoform (cGPX4) localizes to the cytoplasm. UniProt subcellular location vocabulary supports this. Reason: Valid annotation. The cytoplasmic isoform is well-documented and is the most broadly expressed isoform responsible for ferroptosis suppression. GO:0005829 (cytosol) is more specific and also annotated. Supporting Evidence: PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate annotation for mitochondrial localization based on orthology to mouse GPX4. Reason: Valid annotation. Mitochondrial localization of the mGPX4 isoform is well-established. Supporting Evidence: file:human/GPX4/GPX4-deep-research-falcon.md mGPX4 targets mitochondria and preserves mitochondrial membrane integrity |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: GPX4 participates in lipid metabolism by reducing lipid hydroperoxides, thereby modifying oxidized lipids. Reason: While GPX4 does act on lipid substrates (phospholipid hydroperoxides), the annotation to "lipid metabolic process" is somewhat broad. The more informative annotations are the specific MF term (GO:0047066) and the lipoxygenase pathway (GO:0019372). This is a valid but peripheral annotation. Supporting Evidence: PMID:36608588 GPX4 reduces complex lipid hydroperoxides, thus protecting cells from lipid peroxidation and ferroptosis |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000120 | ACCEPT | Summary: GPX4 is a key component of cellular response to oxidative stress through its antioxidant activity. Reason: Valid annotation. This is a parent term of GO:0034599 (cellular response to oxidative stress), which is also annotated with IBA evidence. Both are appropriate. Supporting Evidence: PMID:11115402 the increase in hydroperoxide tone (a situation found under oxidative stress or selenium deficiency or on incubation with 12-HPETE) partly diverts the 12-lipoxygenase pathway from the reduction route to the isomerization route |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | ACCEPT | Summary: GPX4 is an oxidoreductase that reduces hydroperoxides while oxidizing glutathione. Reason: This is a valid high-level MF annotation. GPX4 catalyzes a redox reaction (EC:1.11.1.12). More specific child terms are also annotated. Supporting Evidence: PMID:36608588 The GPXs are important for reducing hydroperoxides in a glutathione-consuming manner |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the IBA annotation for the core molecular function. Reason: This is the core MF of GPX4. Multiple evidence types supporting this annotation are appropriate. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide |
| GO:0098869 cellular oxidant detoxification | IEA GO_REF:0000120 | ACCEPT | Summary: GPX4 detoxifies lipid hydroperoxides, which are oxidant species that can propagate membrane damage. Reason: This is an accurate biological process annotation for GPX4's function in reducing lipid peroxides, thereby detoxifying these oxidants. This is inferred from the MF annotations (GO:0004601, GO:0004602, GO:0047066). Supporting Evidence: PMID:36608588 GPX4 reduces complex lipid hydroperoxides, thus protecting cells from lipid peroxidation and ferroptosis |
| GO:0005634 nucleus | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate annotation for nuclear localization via Ensembl Compara orthology. Reason: Valid annotation. Nuclear localization of nGPX4 is well-established, particularly in spermatogenesis. Supporting Evidence: PMID:21630459 Generating a catalogue of sperm nuclear proteins is an important first step towards the clarification of the function of the paternal chromatin |
| GO:0005635 nuclear envelope | IEA GO_REF:0000107 | UNDECIDED | Summary: Nuclear envelope localization inferred from mouse ortholog. This is more specific than the nucleus annotation. Reason: While nuclear localization of nGPX4 is well-established, specific localization to the nuclear envelope requires verification. I cannot access the primary evidence supporting this specific localization. The annotation may be valid but needs experimental confirmation for human GPX4. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Cytosolic localization inferred from mouse ortholog via Ensembl Compara. Reason: Cytosolic localization of cGPX4 is well-established experimentally (see PMID:11115402 IDA annotation). This IEA annotation is consistent with experimental evidence. Supporting Evidence: PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0008430 selenium binding | IEA GO_REF:0000107 | MODIFY | Summary: GPX4 contains selenocysteine (Sec46) at its active site, which incorporates selenium covalently. Reason: While GPX4 does contain selenium as selenocysteine, "selenium binding" may not be the most accurate term. Selenocysteine is a genetically encoded amino acid, not a bound cofactor. The term could be misleading. However, if the term is defined to include selenoproteins, it may be acceptable. Consider whether a more specific annotation exists for selenoprotein status. Proposed replacements: oxidoreductase activity |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This annotation is inferred from rat ortholog (P36970) via Ensembl Compara. Reason: GPX4 expression may be regulated by estradiol, but this represents a regulatory/upstream response rather than a core function of GPX4. This is a peripheral annotation describing gene regulation rather than the protein's intrinsic function. |
| GO:0110076 negative regulation of ferroptosis | IEA GO_REF:0000107 | ACCEPT | Summary: GPX4 is the central enzymatic suppressor of ferroptosis. The deep research states GPX4 is the central effector of the system xc-/GSH/GPX4 axis and is the key suppressor of ferroptosis by detoxifying PUFA-containing phospholipid hydroperoxides (GPX4-deep-research-falcon.md). Reason: This is one of the most important biological process annotations for GPX4. The role of GPX4 in suppressing ferroptosis is now considered a core function, supported by extensive literature including PMID:24439385 (Yang et al., Cell 2014). Supporting Evidence: PMID:24439385 GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms |
| GO:0042759 long-chain fatty acid biosynthetic process | TAS Reactome:R-HSA-9018676 | MODIFY | Summary: This annotation comes from Reactome pathway "Biosynthesis of D-series resolvins." GPX4 reduces 17-HpDHA to 17-HDHA in resolvin biosynthesis. Reason: While GPX4 participates in resolvin biosynthesis by reducing hydroperoxide intermediates, the annotation to "long-chain fatty acid biosynthetic process" is misleading. GPX4 is not synthesizing fatty acids; it is reducing hydroperoxide derivatives. A more accurate annotation would be related to lipid peroxide reduction or specialized proresolving mediator biosynthesis. Proposed replacements: lipid metabolic process |
| GO:0042759 long-chain fatty acid biosynthetic process | TAS Reactome:R-HSA-9018896 | MODIFY | Summary: Duplicate annotation from Reactome pathway for E-series resolvins. Reason: Same issue as above - GPX4 reduces hydroperoxide intermediates but is not directly synthesizing fatty acids. Proposed replacements: lipid metabolic process |
| GO:0042759 long-chain fatty acid biosynthetic process | TAS Reactome:R-HSA-9020265 | MODIFY | Summary: Duplicate annotation from Reactome pathway for aspirin-triggered D-series resolvins. Reason: Same issue as above - GPX4 reduces hydroperoxide intermediates but is not directly synthesizing fatty acids. Proposed replacements: lipid metabolic process |
| GO:0042759 long-chain fatty acid biosynthetic process | TAS Reactome:R-HSA-9023661 | MODIFY | Summary: Duplicate annotation from Reactome pathway for E-series 18(R)-resolvins. Reason: Same issue as above - GPX4 reduces hydroperoxide intermediates but is not directly synthesizing fatty acids. Proposed replacements: lipid metabolic process |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | TAS Reactome:R-HSA-9018868 | ACCEPT | Summary: Reactome reaction showing GPX4-2 reduces 18(S)-HpEPE to 18(S)-HEPE. Reason: This is the core MF annotation. Reactome reactions provide additional traceable evidence for this activity. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | TAS Reactome:R-HSA-9018895 | ACCEPT | Summary: Reactome reaction showing GPX4-2 reduces 18(R)-HpEPE to 18(R)-HEPE. Reason: Valid additional evidence for core MF. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | TAS Reactome:R-HSA-9020271 | ACCEPT | Summary: Reactome reaction showing GPX4-2 reduces 17(R)-Hp-DHA to 17(R)-HDHA. Reason: Valid additional evidence for core MF. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | TAS Reactome:R-HSA-9020273 | ACCEPT | Summary: Reactome reaction showing GPX4-2 reduces 17(S)-Hp-DHA to 17(S)-HDHA. Reason: Valid additional evidence for core MF. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | IDA PMID:40281343 PSAT1 impairs ferroptosis and reduces immunotherapy efficacy... | ACCEPT | Summary: Direct experimental evidence from study on GPX4 hydroxylation affecting ferroptosis and immunotherapy efficacy. Reason: IDA evidence for core MF is highly valuable. This publication provides direct assay evidence for this activity. Supporting Evidence: PMID:40281343 PSAT1 elevates GPX4 stability by promoting alpha-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation |
| GO:0110076 negative regulation of ferroptosis | IDA PMID:40281343 PSAT1 impairs ferroptosis and reduces immunotherapy efficacy... | ACCEPT | Summary: Direct experimental evidence that GPX4 negatively regulates ferroptosis, from a study on how PSAT1 affects ferroptosis via GPX4 hydroxylation. Reason: This is a core biological process for GPX4. IDA evidence strongly supports this annotation. Supporting Evidence: PMID:40281343 In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteome study defining a high-confidence mitochondrial protein set (MitoCoP). GPX4 is likely included in the dataset but is not explicitly listed in the cached text. Reason: This HTP study is a mitochondrial proteome resource; while the cached text does not list GPX4 explicitly, mitochondrial localization is independently supported by isoform evidence and other annotations. Accept as consistent supporting evidence. Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP) |
| GO:0004602 glutathione peroxidase activity | IDA PMID:36608588 Side-by-side comparison of recombinant human glutathione per... | ACCEPT | Summary: PMID:36608588 directly compared recombinant human GPX1, GPX2, and GPX4 and demonstrated that GPX4 can reduce H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide, albeit with lower efficiency than GPX1. Reason: Direct experimental evidence from purified recombinant enzyme assays. This is high-quality IDA evidence supporting glutathione peroxidase activity. Supporting Evidence: PMID:36608588 small soluble hydroperoxides such as H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide were reduced by all three isoforms, but with approximately 10-fold higher efficiency for GPX1 in comparison to GPX2 and GPX4 |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | IDA PMID:36608588 Side-by-side comparison of recombinant human glutathione per... | ACCEPT | Summary: This key study demonstrated that GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide among GPX1, GPX2, and GPX4, providing direct biochemical evidence for GPX4's unique specificity. Reason: This is the definitive IDA evidence for GPX4's core molecular function. The study directly compared substrate specificities of recombinant human GPXs. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2161959 | ACCEPT | Summary: Reactome reaction for 12R-HpETE reduction to 12R-HETE by GPX1/2/4 places the activity in the cytosol. Reason: Cytosolic localization of cGPX4 is well-established and consistent with IDA evidence from PMID:11115402. Supporting Evidence: PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2161999 | ACCEPT | Summary: Duplicate Reactome annotation for 12S-HpETE reduction. Reason: Valid supporting evidence for cytosolic localization. Supporting Evidence: PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0005829 cytosol | IDA PMID:11115402 Evidence for the presence of phospholipid hydroperoxide glut... | ACCEPT | Summary: PMID:11115402 demonstrated presence of PHGPx in the cytosol of human platelets. Reason: This is direct experimental evidence for cytosolic localization of GPX4 in human cells (platelets). Supporting Evidence: PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0019369 arachidonate metabolic process | IDA PMID:11115402 Evidence for the presence of phospholipid hydroperoxide glut... | ACCEPT | Summary: PMID:11115402 demonstrated GPX4 involvement in arachidonic acid metabolism in platelets, specifically in reducing 12-HpETE produced by 12-lipoxygenase. Reason: This is a core biological process for GPX4, particularly in platelets. The study showed that PHGPx/GPX4 regulates the 12-lipoxygenase pathway of arachidonate metabolism. Supporting Evidence: PMID:11115402 The 12-lipoxygenase pathway of arachidonic acid metabolism in platelets and other cells is bifurcated into a reduction route yielding 12-hydroxyeicosatetraenoic acid (12-HETE) and an isomerization route forming hepoxilins |
| GO:0019372 lipoxygenase pathway | IDA PMID:11115402 Evidence for the presence of phospholipid hydroperoxide glut... | ACCEPT | Summary: Direct experimental evidence from PMID:11115402 showing GPX4 involvement in regulating the 12-lipoxygenase pathway. Reason: High-quality IDA evidence for a core biological process. GPX4 determines the balance between reduction (to 12-HETE) and isomerization (to hepoxilins) routes in the lipoxygenase pathway. Supporting Evidence: PMID:11115402 We therefore believe that both GPx-1 and PHGPx are involved in the regulatory network of the 12-lipoxygenase pathway in platelets and other mammalian cells |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | IDA PMID:11115402 Evidence for the presence of phospholipid hydroperoxide glut... | ACCEPT | Summary: PMID:11115402 provided direct evidence for PHGPx activity in human platelets. Reason: Core MF with IDA evidence. This study was among the first to demonstrate PHGPx activity in human cells. Supporting Evidence: PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9018868 | ACCEPT | Summary: Reactome reaction placing GPX4 activity in cytosol for resolvin biosynthesis. Reason: Valid supporting evidence for cytosolic localization. Supporting Evidence: PMID:11115402 Here we show for the first time the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) protein and its activity in platelets |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9018895 | ACCEPT | Summary: Duplicate Reactome annotation for cytosolic localization. Reason: Valid supporting evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9020271 | ACCEPT | Summary: Duplicate Reactome annotation for cytosolic localization. Reason: Valid supporting evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9020273 | ACCEPT | Summary: Duplicate Reactome annotation for cytosolic localization. Reason: Valid supporting evidence. |
| GO:0006979 response to oxidative stress | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation inferred from pig GPX4 (P36968). Reason: Valid annotation based on sequence similarity to well-characterized pig ortholog. The biological process is core to GPX4 function. Supporting Evidence: PMID:11115402 the increase in hydroperoxide tone (a situation found under oxidative stress or selenium deficiency or on incubation with 12-HPETE) partly diverts the 12-lipoxygenase pathway from the reduction route to the isomerization route |
| GO:0007283 spermatogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS annotation inferred from mouse GPX4 (O70325), but specific supporting evidence is not present in cached publications. Reason: Unable to access a primary source in the cache that directly supports GPX4 involvement in spermatogenesis; needs a publication with explicit evidence. |
| GO:0047066 phospholipid-hydroperoxide glutathione peroxidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation inferred from pig GPX4 (P36968). Reason: Core MF annotation. While IDA evidence is also available, ISS provides additional supporting evidence based on conserved function across species. Supporting Evidence: PMID:36608588 GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide |
| GO:0005515 protein binding | IPI PMID:23355646 Identification of sperm head proteins involved in zona pellu... | REMOVE | Summary: This annotation from a sperm proteomic study identifies GPX4 interactions with zona pellucida binding proteins. The interacting proteins are P21754 (ZP3 receptor), Q05996 (PACRG), and Q12836 (ZP4). Reason: "Protein binding" (GO:0005515) is an uninformative term that tells us nothing about GPX4's actual function. The study identifies potential interactors in sperm but does not demonstrate a specific binding function. Per curation guidelines, this term should be avoided in favor of more informative annotations. The interaction data may be better captured in protein interaction databases rather than GO. Supporting Evidence: PMID:23355646 We identified proteins that are glycolytic enzymes such as pyruvate kinase 3, enolase 1, glyceraldehyde-3-phosphate dehydrogenase, aldolase A, triosephosphate isomerase, detoxification enzymes such as GSTM or phospholipid hydroperoxide glutathione peroxidase, ion channels such as VDAC2 |
| GO:0004602 glutathione peroxidase activity | IMP PMID:17630701 Structural basis for catalytic activity and enzyme polymeriz... | ACCEPT | Summary: PMID:17630701 solved the crystal structure of human GPX4 and characterized mutants. Multiple mutations of the catalytic triad indicated its functional importance. U46C and U46A mutants showed loss of enzyme activity. Reason: Mutational analysis provides strong IMP evidence for glutathione peroxidase activity. The study demonstrated that mutations in the catalytic triad (including the selenocysteine at position 46) abolish enzyme activity. Supporting Evidence: PMID:17630701 Multiple mutations of the catalytic triad indicated its functional importance |
| GO:0032991 protein-containing complex | IMP PMID:17630701 Structural basis for catalytic activity and enzyme polymeriz... | KEEP AS NON CORE | Summary: PMID:17630701 demonstrated GPX4 tendency toward polymerization and formation of higher-order complexes. Reason: GPX4 does form oligomers/polymers, but this is a structural property rather than its core enzymatic function. The polymerization may have functional significance (moonlighting function in sperm) but is peripheral to the peroxidase activity. Supporting Evidence: PMID:17630701 Like the wild-type enzyme, the U46C mutant exhibits a strong tendency toward protein polymerization, which was prevented by reductants |
| GO:0042802 identical protein binding | IMP PMID:17630701 Structural basis for catalytic activity and enzyme polymeriz... | KEEP AS NON CORE | Summary: PMID:17630701 showed GPX4 self-association leading to polymerization. Site-directed mutagenesis identified specific cysteine residues involved in polymer formation. Reason: Self-binding leading to polymerization is a documented property of GPX4, but this is more informative than the generic "protein binding" term. However, it represents a structural/moonlighting property rather than the core enzymatic function. Supporting Evidence: PMID:17630701 Site-directed mutagenesis suggested involvement of the catalytic C46 and surface exposed C10 and C66 in polymer formation |
| GO:0051258 protein polymerization | IMP PMID:17630701 Structural basis for catalytic activity and enzyme polymeriz... | KEEP AS NON CORE | Summary: PMID:17630701 demonstrated that GPX4 undergoes polymerization via intermolecular disulfide bonds, particularly under oxidizing conditions. Reason: GPX4 polymerization is a documented moonlighting function, potentially relevant to its role as a structural component in sperm. This is not the core enzymatic function but is a validated biological process. Supporting Evidence: PMID:17630701 Among GPx-isoforms, GPx4 is unique because of its capability to reduce complex lipid hydroperoxides and its tendency toward polymerization, but the structural basis for these properties remained unclear |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | ACCEPT | Summary: Sperm nucleus proteomics study reporting a catalogue of nuclear proteins; GPX4 is not explicitly listed in the cached text. Reason: This HDA study profiles sperm nuclear proteins. Although GPX4 is not listed in the cached text, nuclear localization is consistent with isoform evidence in other annotations. Accept as supportive but note the gene-specific evidence may be in supplementary tables. Supporting Evidence: PMID:21630459 With this approach, 403 different proteins have been identified from the isolated sperm nuclei |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | UNDECIDED | Summary: Urinary exosome proteomics study, but GPX4 is not mentioned in the cached full text. Reason: Unable to verify GPX4 inclusion in the accessible publication text; evidence may be restricted to supplementary tables not available in the cache. Supporting Evidence: PMID:19056867 Overall, the analysis identified 1132 proteins unambiguously, including 177 that are represented on the Online Mendelian Inheritance in Man database of disease-related genes |
| GO:0006644 phospholipid metabolic process | TAS PMID:8039723 Cloning and sequencing of the cDNA encoding a human testis p... | ACCEPT | Summary: The original cloning paper for human GPX4 from testis. The annotation to phospholipid metabolic process reflects GPX4's action on phospholipid hydroperoxides. Reason: GPX4 directly modifies phospholipid hydroperoxides, which is a form of phospholipid metabolism. This is more specific than "lipid metabolic process" and accurately reflects GPX4's substrate preference. Supporting Evidence: PMID:8039723 A human cDNA that encodes a polypeptide that has 94% deduced amino-acid sequence identity to porcine phospholipid hydroperoxide glutathione peroxidase was cloned from a testis library |
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Download this section (compressed HTML)Q: What is the relative contribution of each GPX4 isoform (cGPX4, mGPX4, nGPX4) to ferroptosis resistance in different cell types?
Q: What are the specific regulatory mechanisms controlling GPX4 expression and stability under oxidative stress conditions?
Experiment: Isoform-specific knockdown/knockout studies to determine relative contributions to ferroptosis resistance in various cell types
Hypothesis: Different GPX4 isoforms have distinct contributions to ferroptosis resistance depending on cell type
Experiment: Detailed characterization of GPX4's role in resolvin biosynthesis using purified enzyme with defined lipid substrates
Hypothesis: GPX4 stereospecifically reduces hydroperoxide intermediates in resolvin biosynthesis pathways
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