The GLS gene (Glutaminase) encodes the enzyme glutaminase, which catalyzes the hydrolysis of glutamine to glutamate. This reaction is crucial for brain metabolism, neurotransmitter synthesis, and cellular energy production. GLS is implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).
| Attribute |
Value |
| Symbol |
GLS |
| Full Name |
Glutaminase (Kidney isoform) |
| Chromosomal Location |
2q32.2 |
| NCBI Gene ID |
2744 |
| OMIM ID |
138280 |
| Ensembl ID |
ENSG00000115419 |
| UniProt ID |
O94925 |
| Protein Size |
598 amino acids |
| Molecular Weight |
~65 kDa |
GLS is a homotetrameric enzyme:
- N-terminal Domain: Glutamine binding
- Catalytic Domain: Hydrolysis reaction center
- C-terminal Domain: Regulatory interactions
- NAD+ Binding Site: Allosteric regulation
- KGA (Kidney-type Glutaminase): Full-length, widely expressed
- GAC (Glutaminase C): Truncated, highly expressed in brain
- LGA: Liver isoform
- Glutamine Hydrolysis: GLS converts glutamine to glutamate
- Tricarboxylic Acid Cycle: Provides anaplerotic substrate
- Glutamate Pool Maintenance: Maintains neurotransmitter glutamate
- Glutamate Synthesis: Produces neurotransmitter glutamate
- GABA Synthesis: Glutamate is precursor for GABA
- Ammonia Detoxification: Part of nitrogen metabolism
- Anaplerosis: Supplies intermediates for TCA cycle
- Astrocyte Function: Critical for astrocyte metabolism
- Neuronal Support: Supports neuronal energy needs
GLS is expressed throughout the brain:
Expression is cell-type specific and regulated by metabolic demand.
- Glutamate Dysregulation: Altered glutaminase activity in AD brain
- Excitotoxicity: Contributes to glutamate-mediated toxicity
- Energy Metabolism: Impaired brain glucose metabolism
- Therapeutic Target: GLS inhibitors being investigated
- Dopaminergic Neurons: Altered glutamate metabolism in SNc
- Excitotoxicity: Contributes to neuron death
- Mitochondrial Dysfunction: Links to energy deficits
- Motor Neuron Vulnerability: Elevated GLS in motor neurons
- Excitotoxicity: Excess glutamate contributes to toxicity
- Therapeutic Potential: GLS inhibitors show promise
- Mutant Huntingtin: Alters glutaminase regulation
- Metabolic Dysfunction: Contributes to energy deficits
| Drug/Compound |
Mechanism |
Status |
| BPTES |
Allosteric GLS inhibitor |
Research |
| CB-839 |
GLS inhibitor |
Clinical trials (cancer) |
| Compound 968 |
GAC-selective inhibitor |
Preclinical |
| DON (6-Diazo-5-oxo-L-norleucine) |
Irreversible inhibitor |
Research |
GLS is regulated by:
- Allosteric Activation: ADP, phosphate activate
- Allosteric Inhibition: Glutamate,product inhibition
- Transcriptional Regulation: p53, c-Myc
- Post-translational Modification: Phosphorylation, acetylation
GLS connects multiple metabolic pathways:
- Glutamine → Glutamate → TCA Cycle
- Glutamate → GABA (GABA shunt)
- Glutamine → Glutathione synthesis