GCLM: Glutamate-Cysteine Ligase Modifier Subunit
Key regulator of glutathione synthesis and oxidative stress response
Gene Information Card
| Symbol | GCLM |
|---|---|
| Full Name | Glutamate-Cysteine Ligase, Modifier Subunit |
| Gene Type | Protein coding |
| Chromosomal Location | 1p22.1 |
| NCBI Gene ID | 2730 ncbi.nlm.nih.gov/gene/2730 |
| Ensembl ID | ENSG00000123909 |
| UniProt ID | P48507 |
| OMIM ID | 601176 |
| HGNC ID | 4312 |
| Aliases | GLCLR, GCSM, GCS light chain |
Description
GCLM encodes the modifier (light) subunit of glutamate-cysteine ligase (GCL), the first and rate-limiting enzyme in glutathione (GSH) biosynthesis. The catalytic subunit (GCLC) forms the holoenzyme with GCLM, which increases the catalytic efficiency and reduces the Km for glutamate. GCLM is essential for maintaining cellular GSH levels, protecting against oxidative stress, and regulating redox homeostasis. Expression is induced by oxidative stress via NRF2/KEAP1 signaling.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency | Loss-of-function mutations in GCLM impair GSH synthesis, leading to reduced red blood cell antioxidant capacity and hemolysis. | ClinVar, OMIM |
| Myocardial infarction | GCLM polymorphisms (e.g., rs41303970) are associated with altered GSH levels and increased risk of myocardial infarction in some populations. | NCBI Gene, PubMed |
| Schizophrenia | Reduced GCLM expression and GSH levels in the prefrontal cortex are linked to oxidative stress and NMDA receptor hypofunction in schizophrenia. | PubMed, OMIM |
| Cancer (multiple types) | GCLM overexpression in various cancers (e.g., lung, breast, ovarian) confers resistance to chemotherapy and radiotherapy by enhancing GSH-mediated detoxification. | COSMIC, PubMed |
| Parkinson's disease | Decreased GCLM activity and GSH depletion in substantia nigra contribute to dopaminergic neuron vulnerability to oxidative damage. | PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | High |
| Kidney | 9.8 | High |
| Lung | 6.2 | Medium |
| Brain | 4.1 | Medium |
| Heart | 3.5 | Medium |
| Skeletal Muscle | 2.0 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 15.3 | Hepatocellular carcinoma cell line |
| A549 | 8.7 | Lung adenocarcinoma cell line |
| MCF7 | 6.4 | Breast cancer cell line |
| SH-SY5Y | 4.2 | Neuroblastoma cell line |
| K562 | 3.1 | Chronic myeloid leukemia cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.473C>T (p.Thr158Ile) | Missense | Rare | Reduced GCL activity and GSH levels; associated with hemolytic anemia |
| c.1A>G (p.Met1Val) | Start loss | Rare | Loss of protein expression; severe GSH deficiency |
| c.588+1G>A | Splice donor | Rare | Skipping of exon 5; frameshift and premature truncation |
| rs41303970 (c.-129C>T) | Promoter | Common (MAF ~0.15) | Reduced promoter activity; associated with myocardial infarction risk |
Mutation functional classification
Loss of Function (LOF)
Missense, nonsense, frameshift, and splice-site mutations that reduce GCLM protein expression or catalytic efficiency, leading to decreased GSH synthesis and increased oxidative stress.
Gain of Function (GOF)
Not well documented; amplification or overexpression of GCLM in cancers may confer gain-of-function by increasing GSH levels and chemoresistance.
Dominant Negative (DN)
No dominant-negative mutations reported; GCLM is a regulatory subunit and loss of one allele may be compensated by the other.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Glutathione metabolism (KEGG: hsa00480)
• NRF2-ARE signaling (Reactome: R-HSA-9759194)
• Metabolism of amino acids and derivatives (Reactome: R-HSA-71291)
• Oxidative stress response (WikiPathways: WP408)
Protein Summary
GCLM (Glutamate-Cysteine Ligase Modifier Subunit) is a 274-amino acid protein (31 kDa) that serves as the regulatory subunit of glutamate-cysteine ligase (GCL). It forms a heterodimer with the catalytic subunit GCLC, enhancing the enzyme's affinity for glutamate and overall catalytic efficiency. GCLM is predominantly cytosolic and is highly expressed in liver and kidney, tissues with high GSH turnover. The protein contains no known transmembrane domains or signal peptides. Post-translational modifications include phosphorylation and S-glutathionylation, which modulate its activity. GCLM is a key target of the NRF2 transcription factor, and its expression is upregulated in response to oxidative stress, electrophiles, and chemopreventive agents.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GCLM Knockout HEK293 Cell Line | EDJ-KQ1587 | Human | 2730 | Details Get a Quote |
| GCLM Knockout A-549 Cell Line | EDJ-KQ22591 | Human | 2730 | Details Get a Quote |
| GCLM Knockout HCT 116 Cell Line | EDJ-KQ22593 | Human | 2730 | Details Get a Quote |
| GCLM Knockout HeLa Cell Line | EDJ-KQ22594 | Human | 2730 | Details Get a Quote |
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