GSR encodes glutathione-disulfide reductase (glutathione reductase, GR; EC 1.8.1.7), an FAD-dependent, NADPH-using homodimeric flavoenzyme of the class-I pyridine nucleotide-disulfide oxidoreductase family. It catalyzes the reduction of oxidized glutathione (glutathione disulfide, GSSG) to two molecules of reduced glutathione (GSH) using NADPH, and constitutes the major mechanism maintaining the high cellular GSH:GSSG ratio that underpins antioxidant defense and thiol redox homeostasis. Each subunit binds one FAD; catalysis proceeds via a redox-active active-site disulfide and electron flow from NADPH through FAD. The enzyme is dually targeted to the cytosol and mitochondria through alternative initiation/splicing, with distinct mitochondrial and cytoplasmic isoforms. In humans, biallelic loss-of-function causes congenital non-spherocytic hemolytic anemia, with hemolytic crises triggered by oxidative stress or ingestion of fava beans (favism).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004362 glutathione-disulfide reductase (NADPH) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of GSR. The phylogenetic (IBA) inference is fully concordant with the UniProt catalytic activity and with direct experimental and structural evidence for the human enzyme. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Reaction=2 glutathione + NADP(+) = glutathione disulfide + NADPH + |
| GO:0045454 cell redox homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: By regenerating GSH from GSSG, GSR maintains the cellular thiol redox environment. Appropriate core biological process, consistent with UniProt. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Constitutes the major mechanism to maintain |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: The mitochondrial isoform (P00390-1) carries an N-terminal transit peptide and is targeted to mitochondria, where GR regenerates GSH in the matrix. Consistent with UniProt subcellular location and Reactome mitochondrial matrix localization. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Mitochondrial]: Mitochondrion. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: The cytoplasmic isoform (P00390-2, produced by alternative initiation) localizes to the cytosol, where GR maintains the cytosolic GSH:GSSG ratio. Also supported by HPA IDA and Reactome. A core site of action. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Cytoplasmic]: Cytoplasm. |
| GO:0006749 glutathione metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: GSR is central to glutathione metabolism, specifically the regeneration (recycling) arm that reduces GSSG back to GSH. Note this is glutathione recycling, not de-novo biosynthesis. Core biological process. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Catalyzes the reduction of glutathione disulfide (GSSG) to |
| GO:0034599 cellular response to oxidative stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GSR sustains GSH-based antioxidant defense and its deficiency manifests as oxidative-stress-triggered hemolysis, so a role in the oxidative-stress response is reasonable. However this is a downstream/consequence process rather than the enzyme's core catalytic role, so it is retained as non-core. Supporting Evidence: file:human/GSR/GSR-uniprot.txt experience hemolytic anemia in response to oxidative stress or |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | Summary: GSR binds one FAD per subunit as an essential redox cofactor, extensively documented in high-resolution crystal structures. A core molecular function. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Note=Binds 1 FAD per subunit. |
| GO:0004362 glutathione-disulfide reductase (NADPH) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (InterPro/RHEA/EC pipeline) assignment of the core catalytic activity, fully consistent with experimental evidence. Redundant with the EXP, TAS and IBA assertions of the same term. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Reaction=2 glutathione + NADP(+) = glutathione disulfide + NADPH + |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: General parent of cytosol, mapped electronically from the UniProt Cytoplasm subcellular-location keyword. Correct but less informative than the cytosol (GO:0005829) annotations; retained as non-core. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Cytoplasmic]: Cytoplasm. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping from the UniProt Mitochondrion subcellular-location keyword; consistent with the mitochondrial isoform and its transit peptide. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Mitochondrial]: Mitochondrion. |
| GO:0006749 glutathione metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic assignment of the core biological process, redundant with the IBA annotation of the same term. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Catalyzes the reduction of glutathione disulfide (GSSG) to |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Correct but high-level grouping term. The specific activity GO:0004362 (glutathione-disulfide reductase) is the informative descendant, making this an over-annotation for capturing the molecular function. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Reaction=2 glutathione + NADP(+) = glutathione disulfide + NADPH + |
| GO:0016668 oxidoreductase activity, acting on a sulfur group of donors, NAD(P) as acceptor | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Correct intermediate grouping term describing the EC 1.8.1.- class, but subsumed by the specific GO:0004362. Over-annotation relative to the precise term. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Reaction=2 glutathione + NADP(+) = glutathione disulfide + NADPH + |
| GO:0045454 cell redox homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic assignment redundant with the IBA annotation of this core biological process. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Constitutes the major mechanism to maintain |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic assignment of FAD binding, redundant with the IBA annotation and directly supported by crystallographic evidence. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Note=Binds 1 FAD per subunit. |
| GO:0050661 NADP binding | IEA GO_REF:0000002 | ACCEPT | Summary: GSR binds NADP(H) as the electron-donating substrate; the UniProt feature table lists multiple NADP(+)-binding residues determined by crystallography. A core molecular function, here supported electronically by InterPro. Supporting Evidence: file:human/GSR/GSR-uniprot.txt /ligand="NADP(+)" |
| GO:0098869 cellular oxidant detoxification | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Logically inferred from the catalytic activity (GO:0004362). GSR contributes indirectly to oxidant detoxification by regenerating GSH used by peroxidases, but it does not itself detoxify oxidants; retained as a non-core downstream process. Supporting Evidence: file:human/GSR/GSR-uniprot.txt Constitutes the major mechanism to maintain |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with the cytoplasmic isoform and Reactome. Supports a core site of action. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Cytoplasmic]: Cytoplasm. |
| GO:0004362 glutathione-disulfide reductase (NADPH) activity | EXP PMID:17185460 Molecular basis of glutathione reductase deficiency in human... | ACCEPT | Summary: Experimental annotation from Kamerbeek et al. (2007), which characterized GR catalytic activity in patient blood cells and recombinant variants and established the molecular basis of GR deficiency. Directly supports the core catalytic function and is the basis for the EC 1.8.1.7 assignment. Cached publication is abstract-only. Supporting Evidence: PMID:17185460 Red blood cells and leukocytes of the patients in family 1 did not |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteome detection, consistent with the mitochondrial isoform and UniProt subcellular location. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Mitochondrial]: Mitochondrion. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71682 | ACCEPT | Summary: Reactome traceable annotation placing the cytosolic GR-catalyzed reaction in the cytosol. Consistent with the cytoplasmic isoform and HPA IDA. Core site. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Cytoplasmic]: Cytoplasm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9761843 | ACCEPT | Summary: Reactome traceable annotation associated with the NFE2L2-dependent GSR expression pathway, again localizing GR to the cytosol. Redundant with the other cytosol annotations but correct. Supporting Evidence: file:human/GSR/GSR-uniprot.txt [Isoform Cytoplasmic]: Cytoplasm. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput mass-spectrometry detection of GSR in prostatic-secretion (urinary) exosomes. Reflects incidental presence in secreted vesicles rather than a catalytic site of action; retained as non-core (not removed, per experimental-lineage HDA policy). Supporting Evidence: PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of GSR in urinary exosomes. As above, an incidental vesicle-proteome localization, not a functional site; retained as non-core. Supporting Evidence: PMID:19056867 the analysis identified 1132 proteins unambiguously |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-3323079 | ACCEPT | Summary: Reactome traceable annotation localizing the GR-catalyzed GSSG reduction to the mitochondrial matrix, consistent with the mitochondrial isoform. A specific, correct site of action. Supporting Evidence: Reactome:R-HSA-3323079 Glutathione reductase (GSR) in the mitochondrial matrix regenerates reduced |
| GO:0009055 electron transfer activity | TAS PMID:947404 Familial deficiency of glutathione reductase in human blood ... | MARK AS OVER ANNOTATED | Summary: Although GR performs intramolecular electron transfer (NADPH to FAD to the active-site disulfide to GSSG), the GO term "electron transfer activity" denotes an electron-carrier role (e.g. in electron transport chains) and is a poor fit for this dedicated disulfide reductase. The specific catalytic function is captured by GO:0004362; this broad TAS is an over-annotation. Not removed (experimental-lineage TAS). Supporting Evidence: PMID:947404 A virtually complete absence of glutathione reductase activity was found in the |
| GO:0004362 glutathione-disulfide reductase (NADPH) activity | TAS PMID:947404 Familial deficiency of glutathione reductase in human blood ... | ACCEPT | Summary: Traceable author statement (Loos et al. 1976) of GR activity in human blood cells, the classic description of familial GR deficiency. Supports the core catalytic function. Cached publication is abstract-only. Supporting Evidence: PMID:947404 A virtually complete absence of glutathione reductase activity was found in the |
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