GCLC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0017109 glutamate-cysteine ligase complex	IBA GO_REF:0000033	ACCEPT	Summary: GCLC is the catalytic subunit of the glutamate-cysteine ligase (GCL) heterodimer, forming a complex with GCLM (the regulatory/modifier subunit). This annotation is well-supported by phylogenetic inference and experimental evidence showing GCLC-GCLM interaction (PMID:9675072, PMID:9841880). Reason: The IBA annotation accurately reflects that GCLC is part of the GCL complex. This is a core function supported by extensive experimental evidence. The heterodimer formation between GCLC and GCLM is essential for optimal enzymatic activity and has been demonstrated by co-expression and purification studies. Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase. PMID:9841880 Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis. file:human/GCLC/GCLC-deep-research-falcon.md model: Edison Scientific Literature
GO:0004357 glutamate-cysteine ligase activity	IBA GO_REF:0000033	ACCEPT	Summary: GCLC possesses glutamate-cysteine ligase activity, catalyzing the ATP-dependent ligation of L-glutamate and L-cysteine to form gamma-L-glutamyl-L-cysteine. This is the primary enzymatic function of the catalytic subunit. Reason: This is the core molecular function of GCLC. The IBA annotation is consistent with extensive experimental evidence including direct enzyme assays with recombinant human protein (PMID:9675072, PMID:12663448). Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase. PMID:12663448 Mar 27. A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production.
GO:0006750 glutathione biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: GCLC catalyzes the first and rate-limiting step in glutathione biosynthesis. The gamma-L-glutamyl-L-cysteine product is subsequently ligated to glycine by glutathione synthetase to produce GSH. Reason: This is a core biological process annotation. GCLC is essential for glutathione biosynthesis as it performs the rate-limiting step. The IBA annotation is strongly supported by the conserved function across eukaryotes. Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase. PMID:12663448 Mar 27. A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MODIFY	Summary: GCLC binds ATP as a substrate for the ligation reaction. The annotation is inferred from UniProt keyword mapping and is too general. Reason: While GCLC does bind nucleotides (specifically ATP as substrate), this term is overly broad. The more specific term GO:0005524 (ATP binding) is already annotated and should be preferred. The direct IDA evidence for ADP binding (GO:0043531) from PMID:24639 provides more precise information. Proposed replacements: ATP binding
GO:0003824 catalytic activity	IEA GO_REF:0000002	MODIFY	Summary: IEA annotation from InterPro domain mapping. GCLC has catalytic activity but this term is too general. Reason: This is an overly broad term. The specific catalytic activity (GO:0004357 glutamate-cysteine ligase activity) is already annotated with experimental evidence and should be used instead. Proposed replacements: glutamate-cysteine ligase activity
GO:0004357 glutamate-cysteine ligase activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for glutamate-cysteine ligase activity from combined automated methods. Duplicates the IBA annotation and experimental IDA annotations. Reason: This is a valid annotation capturing the core molecular function. While redundant with other evidence codes, the IEA annotation reflects automated validation of the core enzymatic function. Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase.
GO:0005524 ATP binding	IEA GO_REF:0000043	ACCEPT	Summary: GCLC requires ATP as a substrate for the ligation reaction. The Km for ATP is 0.4 mM (PMID:9675072). Reason: ATP binding is essential for GCLC function as ATP provides the energy for the ligation reaction. While this is an IEA annotation, it is well-supported by the characterized enzymatic mechanism. Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase.
GO:0006750 glutathione biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for involvement in glutathione biosynthesis from combined automated methods. Duplicates IBA and IDA annotations. Reason: Valid annotation supporting the core biological process. Redundant with experimental evidence but reflects automated validation.
GO:0016874 ligase activity	IEA GO_REF:0000043	MODIFY	Summary: GCLC is indeed a ligase, catalyzing ATP-dependent bond formation. However, this is a parent term of the more specific glutamate-cysteine ligase activity. Reason: This term is valid but too general. The more specific child term GO:0004357 (glutamate-cysteine ligase activity) is already annotated and provides more informative annotation. Proposed replacements: glutamate-cysteine ligase activity
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: GCLC overexpression suppresses TNF-induced apoptosis through maintaining cellular GSH levels and redox status (PMID:10439045). Reason: This is a downstream consequence of GCLC's role in GSH biosynthesis rather than a direct function. GSH maintains cellular redox homeostasis which protects against apoptotic cell death. The effect is indirect - mediated through GSH levels - rather than a direct anti-apoptotic function. Supporting Evidence: PMID:10439045 Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MODIFY	Summary: High-throughput interactome study detecting GCLC-GCLM interaction. Reason: The term "protein binding" is uninformative. The documented interaction is specifically with GCLM (P48507), the regulatory subunit of the GCL complex. The more informative annotation would be the cellular component GO:0017109 (glutamate-cysteine ligase complex) which is already present. Proposed replacements: glutamate-cysteine ligase complex Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: Dual proteome interactome study detecting GCLC-GCLM interaction. Reason: Same rationale as other protein binding annotations - the term is uninformative and the specific interaction is with GCLM to form the GCL complex, which is captured by GO:0017109. Proposed replacements: glutamate-cysteine ligase complex Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MODIFY	Summary: Multimodal cell maps study detecting GCLC-GCLM interaction. Reason: The generic protein binding term should be replaced by the more specific complex annotation that captures the functionally relevant GCLC-GCLM heterodimer formation. Proposed replacements: glutamate-cysteine ligase complex Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0005515 protein binding	IPI PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	MODIFY	Summary: Study demonstrating GCLC-GCLM heterodimer formation through co-expression and purification of the holoenzyme. Reason: This primary literature reference documents the GCLC-GCLM interaction essential for holoenzyme formation. The generic "protein binding" term fails to capture this specific and important functional interaction. Proposed replacements: glutamate-cysteine ligase complex Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase.
GO:0005829 cytosol	IEA GO_REF:0000107	ACCEPT	Summary: GCLC is localized in the cytosol where glutathione biosynthesis occurs. This annotation is transferred from ortholog data. Reason: Cytosolic localization is correct and consistent with the role of GCLC in cytoplasmic GSH synthesis. This is supported by Reactome TAS annotations and the known biochemistry of GSH synthesis.
GO:0006979 response to oxidative stress	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GCLC expression and activity are induced by oxidative stress as part of the cellular antioxidant response. This is mediated through the KEAP1-NRF2 pathway (deep research review). Reason: While GCLC is transcriptionally upregulated in response to oxidative stress (via NRF2) and GSH production protects against oxidative damage, this is a regulatory/response annotation rather than a core function. The core function is GSH biosynthesis. Supporting Evidence: PMID:11972604 Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells.
GO:0007584 response to nutrient	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from rat ortholog. GCLC activity is influenced by cysteine availability which can be nutrient-limited. Reason: This reflects the regulatory context of GCLC rather than its direct function. GSH synthesis is limited by cysteine availability, but response to nutrient is not a core function.
GO:0014823 response to activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. May relate to exercise-induced changes in GSH metabolism. Reason: This is a peripheral annotation describing regulatory context rather than core function. The primary function is enzymatic.
GO:0017109 glutamate-cysteine ligase complex	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for GCLC being part of the GCL heterodimeric complex with GCLM. Reason: Redundant with IBA and IDA annotations but valid. GCLC forms a heterodimer with GCLM constituting the active holoenzyme.
GO:0032869 cellular response to insulin stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from rat ortholog. Insulin signaling may regulate GSH metabolism. Reason: This represents a regulatory input to GCLC expression/activity rather than the core enzymatic function. Pleiotropic cellular responses are secondary to the primary function.
GO:0035729 cellular response to hepatocyte growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer suggesting GCLC responds to HGF. Reason: Peripheral regulatory annotation. Not a core function of GCLC.
GO:0043524 negative regulation of neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GCLC-mediated GSH synthesis protects neurons from apoptotic death. Knockdown of either GCL subunit causes neuronal apoptosis (PMID:16183645). Reason: This is an indirect downstream effect of GSH biosynthesis. While documented experimentally in neurons (PMID:16183645), it represents a tissue-specific consequence rather than a direct anti-apoptotic function. Supporting Evidence: PMID:16183645 2005 Sep 23. Knockdown of glutamate-cysteine ligase by small hairpin RNA reveals that both catalytic and modulatory subunits are essential for the survival of primary neurons.
GO:0044344 cellular response to fibroblast growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. Reason: Peripheral regulatory annotation, not a core function.
GO:0044752 response to human chorionic gonadotropin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. Reason: Tissue-specific regulatory context, not a core function.
GO:0044877 protein-containing complex binding	IEA GO_REF:0000107	MODIFY	Summary: IEA annotation suggesting GCLC binds to protein complexes. Reason: This is vague. The specific relevant complex is the GCLC-GCLM heterodimer, which is better captured by GO:0017109. Proposed replacements: glutamate-cysteine ligase complex
GO:0046686 response to cadmium ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GCLC/GSH is induced by cadmium as a detoxification response. Reason: GSH conjugation is important for heavy metal detoxification, but this represents a regulatory/response context rather than direct cadmium binding or processing by GCLC.
GO:0051409 response to nitrosative stress	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GCLC expression is upregulated by nitrosative stress (e.g., sodium nitroprusside treatment increases GCS activity, PMID:10395918). Reason: This reflects transcriptional regulation of GCLC in response to stress rather than a direct function in nitrosative stress response. Supporting Evidence: PMID:10395918 Regulation of gamma-glutamylcysteine synthetase regulatory subunit (GLCLR) gene expression: identification of the major transcriptional start site in HT29 cells.
GO:0070555 response to interleukin-1	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. Reason: Peripheral regulatory annotation reflecting cytokine-mediated regulation rather than a core function.
GO:0071260 cellular response to mechanical stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. Reason: Peripheral annotation, not a core function.
GO:0071333 cellular response to glucose stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. Reason: Peripheral metabolic regulatory context rather than core function.
GO:0071372 cellular response to follicle-stimulating hormone stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. Reason: Tissue-specific regulatory context, not a core function.
GO:0097069 cellular response to thyroxine stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. Reason: Hormonal regulatory context, not a core function.
GO:2000490 negative regulation of hepatic stellate cell activation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from ortholog transfer. GSH may inhibit hepatic stellate cell activation in fibrosis contexts. Reason: Tissue-specific downstream consequence of GSH production, not a direct or core function of GCLC.
GO:0006750 glutathione biosynthetic process	IDA PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	ACCEPT	Summary: Direct demonstration that recombinant human GCLC catalyzes the first step in glutathione biosynthesis using purified protein. Reason: Core biological process annotation with direct experimental evidence. This study expressed and purified human GCLC and demonstrated its enzymatic function in GSH precursor synthesis. Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase.
GO:0004357 glutamate-cysteine ligase activity	IMP PMID:12663448 A novel missense mutation in the gamma-glutamylcysteine synt...	ACCEPT	Summary: Study of the R127C disease mutation demonstrating decreased enzymatic activity in the mutant, confirming GCLC's role in GCL catalysis. Reason: Core molecular function with mutational evidence. The R127C mutation causes decreased GCL activity and hemolytic anemia, providing genetic evidence for GCLC's essential catalytic role. Supporting Evidence: PMID:12663448 Mar 27. A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production.
GO:0004357 glutamate-cysteine ligase activity	IDA PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	ACCEPT	Summary: Direct biochemical characterization of purified recombinant human GCLC demonstrating glutamate-cysteine ligase activity with kinetic parameters. Reason: Primary experimental evidence for the core molecular function. Km values determined for all substrates confirm the catalytic mechanism. Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase.
GO:0004357 glutamate-cysteine ligase activity	IMP PMID:9841880 Identification of an important cysteine residue in human glu...	ACCEPT	Summary: Site-directed mutagenesis study identifying Cys553 as important for GCLC-GCLM heterodimer formation and enzyme activity. Reason: Mutational evidence supporting the core catalytic function. The C553G mutation reduces holoenzyme activity, confirming the importance of subunit interaction for full activity. Supporting Evidence: PMID:9841880 Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis.
GO:0005515 protein binding	IPI PMID:9841880 Identification of an important cysteine residue in human glu...	MODIFY	Summary: Study demonstrating physical interaction between GCLC and GCLM (GCLR) through site-directed mutagenesis and activity assays. Reason: The generic "protein binding" term fails to capture the specific and functionally important GCLC-GCLM interaction. The complex annotation GO:0017109 is more informative. Proposed replacements: glutamate-cysteine ligase complex Supporting Evidence: PMID:9841880 Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis.
GO:0006536 glutamate metabolic process	IDA PMID:9841880 Identification of an important cysteine residue in human glu...	ACCEPT	Summary: GCLC uses L-glutamate as a substrate. The study characterized glutamate binding and utilization by GCLC. Reason: GCLC directly participates in glutamate metabolism by incorporating glutamate into gamma-glutamylcysteine. This is an accurate annotation of the enzyme's substrate utilization. Supporting Evidence: PMID:9841880 Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis.
GO:0017109 glutamate-cysteine ligase complex	IDA PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	ACCEPT	Summary: Direct demonstration of GCLC-GCLM holoenzyme assembly through co-expression and purification. Reason: Core cellular component annotation with direct experimental evidence. The study co-expressed both subunits and purified the assembled heterodimer. Supporting Evidence: PMID:9675072 Expression and purification of human gamma-glutamylcysteine synthetase.
GO:0017109 glutamate-cysteine ligase complex	IDA PMID:9841880 Identification of an important cysteine residue in human glu...	ACCEPT	Summary: Study demonstrating GCLC-GCLM heterodimer formation and identifying Cys553 as important for the interaction. Reason: Direct experimental evidence for GCLC being part of the GCL complex. Supporting Evidence: PMID:9841880 Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis.
GO:0005829 cytosol	TAS Reactome:R-HSA-5602892	ACCEPT	Summary: Reactome annotation placing GCLC in the cytosol where the GCL reaction occurs. Reason: Cytosolic localization is correct for GCLC and GSH biosynthesis. This is a core localization annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-174367	ACCEPT	Summary: Reactome annotation for the GCL ligation reaction occurring in the cytosol. Reason: Redundant with other cytosol annotations but valid and reflects accurate localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-9760122	ACCEPT	Summary: Reactome annotation for NRF2-dependent GCLC expression, placing the gene product in the cytosol. Reason: Valid cytosolic localization annotation.
GO:0045454 cell redox homeostasis	IDA PMID:10439045 Overexpression of gamma-glutamylcysteine synthetase suppress...	ACCEPT	Summary: GCLC overexpression maintains cellular redox status and suppresses TNF-induced activation of redox-sensitive transcription factors. Reason: GSH produced through GCLC activity is the major cellular antioxidant and maintains redox homeostasis. This annotation reflects the physiological role of GCLC-dependent GSH synthesis. Supporting Evidence: PMID:10439045 Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1.
GO:0000287 magnesium ion binding	IDA PMID:24639 Inactivation of human gamma-glutamylcysteine synthetase by c...	ACCEPT	Summary: GCLC binds magnesium ions as a cofactor. The study detected enzyme-Mg2+ complexes through cystamine inactivation protection experiments. Reason: Magnesium is an essential cofactor for GCL activity. This is a core molecular function annotation supported by direct biochemical evidence. Supporting Evidence: PMID:24639 Inactivation of human gamma-glutamylcysteine synthetase by cystamine.
GO:0006750 glutathione biosynthetic process	IDA PMID:10395918 Regulation of gamma-glutamylcysteine synthetase regulatory s...	ACCEPT	Summary: Study showing GCLC-dependent GSH synthesis in response to oxidative stress. Reason: Core biological process annotation with experimental support showing coordinate regulation of GCLC and GSH levels. Supporting Evidence: PMID:10395918 Regulation of gamma-glutamylcysteine synthetase regulatory subunit (GLCLR) gene expression: identification of the major transcriptional start site in HT29 cells.
GO:0006979 response to oxidative stress	IDA PMID:10395918 Regulation of gamma-glutamylcysteine synthetase regulatory s...	KEEP AS NON CORE	Summary: GCLC expression is upregulated in response to oxidative stress (sodium nitroprusside treatment). Reason: This reflects transcriptional regulation of GCLC in response to oxidative stress rather than a direct function. The core function is GSH biosynthesis. Supporting Evidence: PMID:10395918 Regulation of gamma-glutamylcysteine synthetase regulatory subunit (GLCLR) gene expression: identification of the major transcriptional start site in HT29 cells.
GO:0043531 ADP binding	IDA PMID:24639 Inactivation of human gamma-glutamylcysteine synthetase by c...	ACCEPT	Summary: GCLC binds ADP (product of the ATP-dependent reaction). The study detected enzyme-ADP complexes. Reason: ADP is produced during the GCL reaction and enzyme-ADP complexes were demonstrated experimentally. This supports understanding of the catalytic mechanism. Supporting Evidence: PMID:24639 Inactivation of human gamma-glutamylcysteine synthetase by cystamine.
GO:0004357 glutamate-cysteine ligase activity	IMP PMID:16183645 Knockdown of glutamate-cysteine ligase by small hairpin RNA ...	ACCEPT	Summary: shRNA knockdown of GCLC reduces GCL activity and causes neuronal apoptosis, which is rescued by expressing GCLC cDNA. Reason: Loss-of-function evidence confirming GCLC's essential role in GCL catalytic activity. Rescue experiments validate specificity. Supporting Evidence: PMID:16183645 2005 Sep 23. Knockdown of glutamate-cysteine ligase by small hairpin RNA reveals that both catalytic and modulatory subunits are essential for the survival of primary neurons.
GO:0006536 glutamate metabolic process	IDA PMID:12663448 A novel missense mutation in the gamma-glutamylcysteine synt...	ACCEPT	Summary: Study characterizing GCLC enzymatic parameters including glutamate utilization. Reason: GCLC utilizes glutamate as a substrate and thus participates in glutamate metabolism. Supporting Evidence: PMID:12663448 Mar 27. A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production.
GO:0006750 glutathione biosynthetic process	IMP PMID:12663448 A novel missense mutation in the gamma-glutamylcysteine synt...	ACCEPT	Summary: The R127C disease mutation causes decreased GSH production, confirming GCLC's essential role in glutathione biosynthesis. Reason: Mutational evidence supporting the core biological process annotation. Supporting Evidence: PMID:12663448 Mar 27. A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production.
GO:0097746 blood vessel diameter maintenance	IMP PMID:12598062 Association of polymorphism in glutamate-cysteine ligase cat...	KEEP AS NON CORE	Summary: A GCLC promoter polymorphism (-129T) is associated with impaired coronary endothelium-dependent vasodilation and myocardial infarction. Reason: This is an indirect physiological consequence of reduced GCLC expression and GSH levels on vascular function, not a direct function. The polymorphism affects transcriptional response to oxidative stress. Supporting Evidence: PMID:12598062 Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction.
GO:0004357 glutamate-cysteine ligase activity	IDA PMID:11972604 Oxidant stress induces gamma-glutamylcysteine synthetase and...	ACCEPT	Summary: Direct measurement of GCS activity in bronchial epithelial cells showing induction by oxidative stress. Reason: Core molecular function with direct enzymatic activity measurement. Supporting Evidence: PMID:11972604 Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells.
GO:0006534 cysteine metabolic process	IDA PMID:2294991 Gamma-glutamylcysteine synthetase deficiency and hemolytic a...	ACCEPT	Summary: Study of GCLC deficiency affecting cysteine utilization for GSH synthesis. Km for cysteine was assessed. Reason: GCLC uses cysteine as a substrate and thus participates in cysteine metabolism. This is an accurate annotation. Supporting Evidence: PMID:2294991 Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia.
GO:0006536 glutamate metabolic process	IDA PMID:2294991 Gamma-glutamylcysteine synthetase deficiency and hemolytic a...	ACCEPT	Summary: Study assessing Km for glutamic acid in GCLC deficiency patient samples. Reason: GCLC utilizes glutamate as a substrate and participates in glutamate metabolism. Supporting Evidence: PMID:2294991 Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia.
GO:0006979 response to oxidative stress	IDA PMID:11972604 Oxidant stress induces gamma-glutamylcysteine synthetase and...	KEEP AS NON CORE	Summary: GCLC expression and activity are induced by oxidative stress (menadione treatment) in bronchial epithelial cells. Reason: This annotation reflects the regulatory response of GCLC to oxidative stress rather than a direct function. The core function is GSH synthesis. Supporting Evidence: PMID:11972604 Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells.
GO:0016595 glutamate binding	IDA PMID:9841880 Identification of an important cysteine residue in human glu...	ACCEPT	Summary: Site-directed mutagenesis study examining glutamate binding properties of GCLC. Reason: Glutamate binding is essential for GCLC catalytic function as glutamate is a substrate. This annotation captures a core molecular function. Supporting Evidence: PMID:9841880 Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis.
GO:0043066 negative regulation of apoptotic process	IDA PMID:10439045 Overexpression of gamma-glutamylcysteine synthetase suppress...	KEEP AS NON CORE	Summary: GCLC overexpression suppresses TNF-induced apoptosis and caspase-3 activation. Reason: This is an indirect effect mediated through GSH-dependent maintenance of cellular redox homeostasis. Not a direct anti-apoptotic function of GCLC itself. Supporting Evidence: PMID:10439045 Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:10439045 Overexpression of gamma-glutamylcysteine synthetase suppress...	KEEP AS NON CORE	Summary: GCLC overexpression blocks NF-kappa B-dependent gene transcription by maintaining redox status. Reason: This is an indirect effect mediated through GSH maintaining cellular redox status, which affects redox-sensitive transcription factors. GCLC does not directly regulate transcription. Supporting Evidence: PMID:10439045 Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1.
GO:0004357 glutamate-cysteine ligase activity	IDA PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of gl...	ACCEPT	Summary: Direct measurement of GCS activity in K562 cells showing heat shock induction. Reason: Core molecular function with direct enzymatic activity measurement. Supporting Evidence: PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of glutathione S-conjugate are responsive to heat shock in K562 erythroid cells.
GO:0006750 glutathione biosynthetic process	IDA PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of gl...	ACCEPT	Summary: Study demonstrating GCLC role in glutathione synthesis in response to heat shock. Reason: Core biological process annotation with direct experimental evidence. Supporting Evidence: PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of glutathione S-conjugate are responsive to heat shock in K562 erythroid cells.
GO:0009408 response to heat	IDA PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of gl...	KEEP AS NON CORE	Summary: GCLC activity and mRNA are induced by heat shock in K562 cells. Reason: This reflects transcriptional regulation of GCLC by heat shock rather than a direct heat response function. The core function is GSH synthesis. Supporting Evidence: PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of glutathione S-conjugate are responsive to heat shock in K562 erythroid cells.
GO:0009725 response to hormone	IDA PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of gl...	KEEP AS NON CORE	Summary: GCLC activity is reduced by erythropoietin treatment in K562 cells. Reason: This annotation reflects hormonal regulation of GCLC expression rather than a direct hormone response function. The core function is enzymatic. Supporting Evidence: PMID:8104187 gamma-Glutamylcysteine synthetase and active transport of glutathione S-conjugate are responsive to heat shock in K562 erythroid cells.

Gene Description

Existing Annotations Review

Core Functions

References

Tags

Deep Research

Falcon

📄 View Raw YAML