GCLC (Glutamate-Cysteine Ligase Catalytic Subunit): Genetics, Function, and Clinical Significance
A comprehensive biomedical overview of the GCLC gene, its protein product, associated diseases, expression patterns, and mutational landscape, based on authoritative genomic databases.
Gene Information Card
| Symbol | GCLC |
|---|---|
| Full Name | Glutamate-Cysteine Ligase Catalytic Subunit |
| Gene Type | Protein-coding |
| Chromosomal Location | 6p12.1 |
| NCBI Gene ID | 2729 ncbi.nlm.nih.gov/gene/2729 |
| Ensembl ID | ENSG00000001084 |
| UniProt ID | P48506 |
| OMIM ID | 606857 |
| HGNC ID | 4311 |
| Aliases | GLCL, GCS, Gamma-glutamylcysteine synthetase catalytic subunit |
Description
The GCLC gene encodes the catalytic subunit of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the biosynthesis of glutathione (GSH). Glutathione is a critical cellular antioxidant that protects cells from oxidative stress, detoxifies xenobiotics, and maintains redox homeostasis. The GCLC protein catalyzes the ATP-dependent condensation of L-glutamate and L-cysteine to form gamma-glutamylcysteine, which is subsequently combined with glycine by glutathione synthetase to produce glutathione. GCLC is expressed ubiquitously, with high levels in tissues with significant detoxification and antioxidant demands. Mutations in GCLC can lead to glutathione synthetase deficiency, manifesting as hemolytic anemia, metabolic acidosis, and neurological impairment. The gene is also implicated in susceptibility to various complex diseases, including cardiovascular disease, diabetes, and cancer, due to its role in oxidative stress response.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| Glutathione synthetase deficiency (Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency) | Biallelic loss-of-function mutations in GCLC lead to reduced or absent GCL activity, impairing glutathione synthesis. This results in increased oxidative stress and cellular damage, particularly in red blood cells, leading to hemolytic anemia. The severity of the phenotype correlates with the residual enzyme activity. | ClinVar, OMIM (606857) |
| Myocardial infarction (susceptibility) | Polymorphisms in GCLC, such as the -129C/T promoter variant, may alter gene expression and affect glutathione levels, influencing susceptibility to oxidative stress-related cardiovascular damage. | NCBI Gene, PubMed (via NCBI) |
| Diabetes mellitus (susceptibility) | Variants in GCLC have been associated with altered glutathione levels and increased oxidative stress, which may contribute to insulin resistance and beta-cell dysfunction. | NCBI Gene, PubMed (via NCBI) |
| Various cancers (susceptibility/prognosis) | Altered GCLC expression and activity can influence cellular resistance to oxidative stress and chemotherapy. Upregulation of GCLC is often observed in tumors and is associated with drug resistance and poor prognosis. | COSMIC, PubMed (via NCBI) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Liver | High (e.g., >100) | High |
| Kidney | High (e.g., >50) | High |
| Adrenal Gland | Medium (e.g., 20-50) | Medium |
| Pancreas | Medium (e.g., 20-50) | Medium |
| Lung | Medium (e.g., 10-20) | Medium |
| Skeletal Muscle | Low (e.g., <10) | Low |
| Brain | Low (e.g., <10) | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| HepG2 (Liver) | High | Hepatocellular carcinoma cell line; high expression reflects liver's role in glutathione synthesis. |
| A549 (Lung) | Medium | Lung carcinoma cell line; moderate expression. |
| MCF7 (Breast) | Medium | Breast adenocarcinoma cell line; moderate expression. |
| K562 (Leukemia) | Low | Chronic myelogenous leukemia cell line; lower expression compared to liver-derived lines. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| c.1102C>T (p.Arg368Ter) | Nonsense | Rare (pathogenic) | Introduces a premature stop codon, leading to a truncated, non-functional protein and loss of GCL activity. Associated with severe glutathione synthetase deficiency. |
| c.491G>A (p.Arg164Gln) | Missense | Rare (likely pathogenic) | Substitution of arginine to glutamine at a conserved residue, likely disrupting protein folding or catalytic activity, leading to reduced GCL function. |
| c.-129C>T (promoter) | Promoter variant | Common (polymorphism) | Alters promoter activity, potentially affecting GCLC expression levels. Associated with altered glutathione levels and susceptibility to oxidative stress-related diseases. |
| c.1102C>T (p.Arg368Ter) | Nonsense | Rare (pathogenic) | Introduces a premature stop codon, leading to a truncated, non-functional protein and loss of GCL activity. Associated with severe glutathione synthetase deficiency. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in GCLC, including nonsense, frameshift, and missense variants that disrupt the catalytic site or protein stability, lead to reduced or absent glutamate-cysteine ligase activity. This impairs glutathione biosynthesis, resulting in increased oxidative stress and cellular damage. Biallelic loss-of-function mutations cause hereditary hemolytic anemia.
Gain of Function (GOF)
Gain-of-function mutations in GCLC are not well-documented in the literature. However, promoter polymorphisms that increase GCLC expression could be considered a form of functional upregulation, potentially enhancing glutathione production and cellular antioxidant capacity. This may be beneficial in some contexts but could also contribute to chemotherapy resistance in cancer.
Dominant Negative (DN)
Dominant-negative effects have not been clearly established for GCLC mutations. Since GCLC functions as a holoenzyme with a modifier subunit (GCLM), a mutant catalytic subunit could potentially interfere with the assembly or function of the holoenzyme. However, most pathogenic mutations are recessive, requiring biallelic inactivation to cause disease.
View complete mutation data：
Gene Ontology (GO)
| • ATP binding | • Glutamate-cysteine ligase activity |
| • Catalytic activity | • Protein homodimerization activity |
| • Response to oxidative stress | • Glutathione biosynthetic process |
| • Cellular response to cadmium ion | • Cellular response to hydrogen peroxide |
| • Xenobiotic metabolic process | • Negative regulation of apoptotic process |
Pathways
• Glutathione metabolism
• Metabolism of xenobiotics by cytochrome P450
• Cysteine and methionine metabolism
• Response to oxidative stress (Reactome)
Protein Summary
The GCLC protein (UniProt P48506) is the catalytic subunit of glutamate-cysteine ligase (GCL), a heterodimeric enzyme composed of a catalytic (GCLC) and a modifier (GCLM) subunit. GCLC is a 637-amino acid protein that catalyzes the rate-limiting step in glutathione (GSH) synthesis: the ATP-dependent ligation of L-glutamate and L-cysteine to form gamma-glutamylcysteine. The protein contains an ATP-binding domain and a catalytic domain, and its activity is regulated by feedback inhibition by GSH and by post-translational modifications. GCLC is localized predominantly in the cytosol and is expressed in all tissues, with highest levels in the liver, kidney, and pancreas. Its expression is induced by oxidative stress and various transcription factors, including Nrf2. The protein is essential for maintaining cellular redox balance and protecting against oxidative damage.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GCLC Knockout HEK293 Cell Line | EDJ-KQ3948 | Human | 2729 | Details Get a Quote |
| GCLC Knockout A-549 Cell Line | EDJ-KQ27442 | Human | 2729 | Details Get a Quote |
| GCLC Knockout HCT 116 Cell Line | EDJ-KQ27444 | Human | 2729 | Details Get a Quote |
| GCLC Knockout HeLa Cell Line | EDJ-KQ27445 | Human | 2729 | Details Get a Quote |
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