GCLM

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0035226 glutamate-cysteine ligase catalytic subunit binding	IBA GO_REF:0000033	ACCEPT	Summary: GCLM binds the catalytic subunit GCLC (P48506) to form the GCL heterodimer. This is a core, well-supported molecular function conserved across orthologs (FBgn0046114, MGI:104995, RGD:619871), directly demonstrated experimentally for the human protein (see PMID:9675072, PMID:9841880).
GO:1990609 glutamate-cysteine ligase regulator activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the defining molecular function of GCLM: it binds and modulates glutamate-cysteine ligase, increasing holoenzyme activity, lowering the Km for glutamate/ATP and raising the Ki for feedback inhibition by glutathione. Well supported both phylogenetically and experimentally (PMID:9895302, PMID:9841880). Core function.
GO:0017109 glutamate-cysteine ligase complex	IBA GO_REF:0000033	ACCEPT	Summary: GCLM is a subunit of the glutamate-cysteine ligase heterodimeric complex (GCLC + GCLM; ComplexPortal CPX-2865). Correct and core.
GO:0006750 glutathione biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: GCLM is part of the enzyme catalyzing the first, rate-limiting step of glutathione biosynthesis. Core biological process; well supported.
GO:0006750 glutathione biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to the correct core biological process (glutathione biosynthesis). Redundant with the experimental (IDA/IMP) and IBA annotations to the same term but not wrong.
GO:0035226 glutamate-cysteine ligase catalytic subunit binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to the correct, informative binding function (binds GCLC). Redundant with the IBA and experimental IPI annotations to the same term but not wrong.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput AP-MS (BioPlex 2.0) capture of the GCLM-GCLC interaction (WITH UniProtKB:P48506). Bare "protein binding" is uninformative; the specific, informative version of this interaction is already captured by GO:0035226 (glutamate-cysteine ligase catalytic subunit binding). Retained as an over-annotation rather than removed (experimental IPI).
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: High-throughput binary interactome (HuRI) interaction; WITH UniProtKB:Q9UJX0 (OSGIN1, oxidative stress-induced growth inhibitor 1), not GCLC. Bare "protein binding" is uninformative. OSGIN1 is a plausible redox-pathway partner (also listed in the UniProt INTERACTION block) but the annotation conveys no specific function. Over-annotation; retained (IPI).
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: High-throughput AP-MS (BioPlex 3.0) capture of the GCLM-GCLC interaction (WITH UniProtKB:P48506). Bare "protein binding" is uninformative; GO:0035226 captures this interaction specifically. Over-annotation; retained (experimental IPI).
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: High-throughput multimodal AP-MS cell-mapping study capturing the GCLM-GCLC interaction (WITH UniProtKB:P48506). Bare "protein binding" is uninformative; GO:0035226 captures this specifically. Over-annotation; retained (experimental IPI).
GO:0005515 protein binding	IPI PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	MARK AS OVER ANNOTATED	Summary: Co-expression and purification of the human gamma-GCS holoenzyme showing GCLM assembles with the catalytic subunit GCLC (WITH UniProtKB:P48506). Bare "protein binding" is uninformative; the specific, informative version is GO:0035226 (catalytic subunit binding). Over-annotation; retained (IPI).
GO:0004357 glutamate-cysteine ligase activity	IEA GO_REF:0000107	MODIFY	Summary: This electronic annotation asserts that GCLM "enables" glutamate-cysteine ligase (catalytic) activity. That is misleading for the modifier subunit: GCLM has no ligase activity on its own; catalysis resides in GCLC and GCLM only contributes to holoenzyme activity. The experimental annotation to this term correctly uses the contributes_to qualifier (PMID:16183645). Recommend replacing the standalone catalytic MF with the regulator activity that GCLM actually enables (GO:1990609), keeping the catalytic term only as contributes_to. Proposed replacements: glutamate-cysteine ligase regulator activity
GO:0006979 response to oxidative stress	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: GCLM supports antioxidant defense by driving glutathione synthesis and its gene is induced by oxidative stress (NRF2/ARE target). Reasonable process annotation supported by the experimental IDA to the same term (PMID:10395918). Non-core relative to the enzymatic function.
GO:0007584 response to nutrient	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog (Ensembl Compara). Broad stimulus-response term with no direct human experimental support in the cited evidence; peripheral to GCLM's core enzymatic role.
GO:0014823 response to activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog. Very broad stimulus-response term, peripheral and not informative about GCLM's molecular function. Non-core.
GO:0017109 glutamate-cysteine ligase complex	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to the correct cellular component (GCL complex). Redundant with the IBA and experimental IDA annotations but not wrong.
GO:0035729 cellular response to hepatocyte growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog via Ensembl Compara, based on transcriptional induction of Gclm in a specific stimulus context. Highly specific stimulus-response term with no direct human experimental support here; peripheral to core function.
GO:0035733 hepatic stellate cell activation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog. Cell-type/tissue-specific process not reflecting GCLM's general molecular function; peripheral. Non-core.
GO:0043524 negative regulation of neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Consistent with the observation that GCLM knockdown triggers apoptotic death of primary neurons via glutathione depletion (PMID:16183645), i.e. GCLM activity is anti-apoptotic in neurons. This is a downstream physiological consequence of maintaining glutathione, not a core molecular function. Retained as non-core.
GO:0044344 cellular response to fibroblast growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog; specific stimulus-response term with no direct human experimental support here. Peripheral to core function. Non-core.
GO:0044752 response to human chorionic gonadotropin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog; highly specific stimulus-response term with no direct human experimental support. Peripheral. Non-core.
GO:0046982 protein heterodimerization activity	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: GCLM does form a heterodimer with GCLC, so this is not wrong. However it is a generic term; the informative version of the interaction is captured by GO:0035226 (glutamate-cysteine ligase catalytic subunit binding) and GO:1990609. Over-annotation relative to the specific terms.
GO:0051409 response to nitrosative stress	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Consistent with induction of the GCLM/GLCLR gene and increased glutathione synthesis in response to nitric oxide donors (PMID:10395918), and with the GCL-GSH-NO axis (PMID:12975258). Downstream physiological response, not a core molecular function. Non-core.
GO:0071333 cellular response to glucose stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog; specific stimulus-response term with no direct human experimental support here. Peripheral to core function. Non-core.
GO:0071372 cellular response to follicle-stimulating hormone stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog; highly specific stimulus-response term with no direct human experimental support. Peripheral. Non-core.
GO:0097069 cellular response to thyroxine stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from rodent ortholog; highly specific stimulus-response term with no direct human experimental support. Peripheral. Non-core.
GO:0006750 glutathione biosynthetic process	IDA PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	ACCEPT	Summary: ComplexPortal/UniProt IDA: the reconstituted human gamma-GCS holoenzyme (GCLC + GCLM co-expressed and purified) is active and behaves like native enzyme, directly demonstrating GCLM's participation in glutathione biosynthesis. Core biological process. Supporting Evidence: PMID:9675072 coexpression in Escherichia coli
GO:0017109 glutamate-cysteine ligase complex	IPI PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	ACCEPT	Summary: ComplexPortal IPI documenting GCLM as a subunit of the glutamate-cysteine ligase complex, based on co-expression/purification of the holoenzyme. Core cellular component.
GO:0017109 glutamate-cysteine ligase complex	IDA PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	ACCEPT	Summary: UniProt IDA that GCLM is part of the GCL complex, from purification of the recombinant human holoenzyme. Core cellular component (duplicate of the ComplexPortal IPI on the same paper). Supporting Evidence: PMID:9675072 Intracellular assembly of the holoenzyme occurred without difficulty
GO:0035226 glutamate-cysteine ligase catalytic subunit binding	IPI PMID:9675072 Expression and purification of human gamma-glutamylcysteine ...	ACCEPT	Summary: GCLM binds the catalytic subunit GCLC (WITH UniProtKB:P48506) to form the active holoenzyme, shown by co-expression and purification. Informative, core molecular function.
GO:0017109 glutamate-cysteine ligase complex	IDA PMID:9841880 Identification of an important cysteine residue in human glu...	ACCEPT	Summary: GCLM (regulatory subunit, hGLCLR) is part of the purified human GCL holoenzyme; the study characterizes GCLC-GCLR heterodimer formation. Core cellular component. Supporting Evidence: PMID:9841880 Both recombinant hGLCLC and hGLCL holoenzyme were expressed and
GO:0005829 cytosol	TAS Reactome:R-HSA-174367	ACCEPT	Summary: GCL is a cytosolic enzyme; the GCL-catalyzed ligation of L-Glu to L-Cys is placed in the cytosol by Reactome. Correct subcellular location.
GO:0005829 cytosol	TAS Reactome:R-HSA-5602892	ACCEPT	Summary: Cytosolic localization asserted by Reactome (defective-GCLC reaction context). Correct location; redundant with the other cytosol annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-9760125	ACCEPT	Summary: Cytosolic localization asserted by Reactome (GCLM gene-expression context). Correct location; redundant with the other cytosol annotations.
GO:0005829 cytosol	NAS PMID:9895302 Overexpression of the regulatory subunit of gamma-glutamylcy...	ACCEPT	Summary: Non-traceable author statement that GCLM (GCSl) is cytosolic. Consistent with the known cytosolic localization of GCL. Correct; weak evidence type.
GO:0006536 glutamate metabolic process	IDA PMID:9895302 Overexpression of the regulatory subunit of gamma-glutamylcy...	KEEP AS NON CORE	Summary: Glutamate is a substrate of the GCL reaction, so GCLM's contribution to the holoenzyme places it in glutamate metabolism. This is a broad, accurate but non-core process relative to glutathione biosynthesis, which is the specific pathway. Retained as non-core.
GO:0009410 response to xenobiotic stimulus	IDA PMID:9895302 Overexpression of the regulatory subunit of gamma-glutamylcy...	KEEP AS NON CORE	Summary: GCLM overexpression increased glutathione-based resistance to xenobiotics (doxorubicin, cadmium chloride) in this study; the GCLM gene is a xenobiotic/ARE-inducible target. Downstream physiological response, not a core molecular function. Non-core. Supporting Evidence: PMID:9895302 a potential role for GCSl in resistance towards doxorubicin
GO:0006750 glutathione biosynthetic process	IDA PMID:10395918 Regulation of gamma-glutamylcysteine synthetase regulatory s...	ACCEPT	Summary: GCLM (GLCLR) is required for glutathione synthesis; oxidant induction of GLCLR raises glutathione and GCS activity. Supports the core biological process. Note the paper is chiefly promoter/transcription analysis, but the functional role in GSH synthesis is well established. Supporting Evidence: PMID:10395918 GCSl has a critical role in glutathione synthesis
GO:0006750 glutathione biosynthetic process	IMP PMID:12081989 Polymorphism in the 5'-flanking region of human glutamate-cy...	ACCEPT	Summary: This study is a promoter-polymorphism (-588C/T) genetic association with myocardial infarction, showing the T allele lowers oxidant-inducible GCLM promoter activity (and, in related work, plasma glutathione). It supports GCLM's role in glutathione synthesis indirectly via gene-dosage/expression rather than a direct loss-of-function assay, but the assignment to the core GSH-biosynthesis process is appropriate. Supporting Evidence: PMID:12081989 the T allele showed lower promoter activity
GO:0006979 response to oxidative stress	IDA PMID:10395918 Regulation of gamma-glutamylcysteine synthetase regulatory s...	KEEP AS NON CORE	Summary: GCLM/GLCLR expression and glutathione synthesis are induced by oxidant (nitric oxide donor) stress, linking GCLM to the antioxidant response. Accurate downstream physiological process; non-core relative to the enzymatic function. Supporting Evidence: PMID:10395918 increase glutathione levels by 2-fold, as well as GCS activity by 6-fold
GO:0097746 blood vessel diameter maintenance	IMP PMID:12975258 Polymorphism in glutamate-cysteine ligase modifier subunit g...	KEEP AS NON CORE	Summary: The GCLM -588C/T polymorphism is associated with impaired NO-mediated coronary vasomotor function, supporting a GCL-GSH-NO axis in vascular tone. This is a tissue-level physiological association downstream of glutathione status, not a core molecular function of GCLM. Non-core. Supporting Evidence: PMID:12975258 impairment of endothelium-dependent vasomotor function
GO:0004357 glutamate-cysteine ligase activity	IMP PMID:16183645 Knockdown of glutamate-cysteine ligase by small hairpin RNA ...	ACCEPT	Summary: shRNA knockdown of the modulatory subunit (GCLM) disrupts GCL activity and glutathione levels, showing GCLM contributes to holoenzyme glutamate-cysteine ligase activity. The contributes_to qualifier is the correct way to annotate this catalytic term to the non-catalytic modifier subunit; contrast with the IEA "enables" annotation to the same term, which is over-strong and is proposed for MODIFY. Core (as contributes_to). The paper also shows overexpressing the catalytic (not modulatory) subunit alone raises activity, consistent with GCLM being rate-optimizing rather than catalytic. Supporting Evidence: PMID:16183645 both catalytic and modulatory subunits are essential for the survival of
GO:0006536 glutamate metabolic process	IDA PMID:9841880 Identification of an important cysteine residue in human glu...	KEEP AS NON CORE	Summary: GCLM is part of the GCL holoenzyme that consumes glutamate as a substrate, placing it in glutamate metabolism. Broad, accurate but non-core relative to glutathione biosynthesis. Non-core.
GO:0035226 glutamate-cysteine ligase catalytic subunit binding	IPI PMID:9841880 Identification of an important cysteine residue in human glu...	ACCEPT	Summary: Direct experimental demonstration that GCLM (hGLCLR) binds the catalytic subunit GCLC (WITH UniProtKB:P48506) to form the heterodimer, with GCLC Cys-553 mapped to the interface. Informative, core molecular function. Supporting Evidence: PMID:9841880 cysteine-553 in hGLCLC is involved in heterodimer formation between hGLCLC

Gene Description

Existing Annotations Review

Core Functions

Regulatory (modifier) subunit of glutamate-cysteine ligase: binds the catalytic subunit GCLC and modulates the holoenzyme to increase glutathione synthesis efficiency (lowers Km for glutamate/ATP, raises Ki for GSH feedback inhibition).

Functions in the glutathione biosynthetic process as the regulatory subunit of the rate-limiting enzyme, supporting cellular antioxidant defense.

References

📚 Additional Documentation

Notes

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