GLUL (Glutamate-Ammonia Ligase) - Structure, Function, and Clinical Significance
A comprehensive biomedical overview of the GLUL gene, encoding glutamine synthetase, including genomic context, expression, disease associations, and mutation landscape.
Gene Information Card
| Symbol | GLUL |
|---|---|
| Full Name | glutamate-ammonia ligase |
| Gene Type | protein coding |
| Chromosomal Location | 1q25.3 |
| NCBI Gene ID | 2752 ncbi.nlm.nih.gov/gene/2752 |
| Ensembl ID | ENSG00000135821 |
| UniProt ID | P15104 |
| OMIM ID | 138290 |
| HGNC ID | 4321 |
| Aliases | GS, glutamine synthetase, glutamate--ammonia ligase |
Description
The GLUL gene encodes glutamate-ammonia ligase, also known as glutamine synthetase, a key enzyme that catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine. This reaction plays a central role in nitrogen metabolism, ammonia detoxification, and the regulation of neurotransmitter glutamate/glutamine cycling in the brain. The enzyme is a homooctamer and is expressed in multiple tissues, with highest levels in liver, brain, and kidneys. Mutations in GLUL are associated with congenital glutamine deficiency, a severe autosomal recessive disorder characterized by brain malformations, seizures, and respiratory failure. Additionally, altered GLUL expression has been implicated in various cancers and hepatic encephalopathy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Congenital glutamine deficiency | Biallelic loss-of-function mutations in GLUL lead to reduced glutamine synthetase activity, resulting in impaired glutamine biosynthesis and severe neurological symptoms. | OMIM #610015; ClinVar; PMID: 15805148 |
| Hepatic encephalopathy | Reduced GLUL expression in the brain (astrocytes) impairs ammonia detoxification, contributing to hyperammonemia-induced encephalopathy. | Multiple studies; PMID: 16951165 |
| Glioma | GLUL expression is often downregulated in gliomas, leading to altered glutamate metabolism and tumor progression. | COSMIC; PMID: 23408866 |
| Hepatocellular carcinoma | GLUL expression is frequently elevated in liver cancer, promoting glutamine metabolism and tumor growth. | COSMIC; PMID: 28394367 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 110.2 | High |
| Brain | 58.7 | High |
| Kidney | 45.3 | High |
| Adipose tissue | 20.1 | Medium |
| Lung | 12.4 | Medium |
| Heart | 8.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 120.5 | Liver cancer cell line, high expression |
| U87MG | 15.2 | Glioblastoma cell line, reduced expression |
| A549 | 22.3 | Lung carcinoma cell line, moderate expression |
| HEK293 | 35.7 | Embryonic kidney cells, moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Arg324Cys | Missense | Rare (found in congenital glutamine deficiency) | Loss of enzymatic activity |
| p.Arg341Cys | Missense | Rare (found in congenital glutamine deficiency) | Loss of enzymatic activity |
| p.Arg324His | Missense | Rare (found in congenital glutamine deficiency) | Loss of enzymatic activity |
| c.970C>T | Nonsense | Rare (found in congenital glutamine deficiency) | Premature truncation, loss of function |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic mutations in GLUL are loss-of-function, leading to reduced or absent glutamine synthetase activity. This results in congenital glutamine deficiency with severe neurological manifestations.
Gain of Function (GOF)
No clear gain-of-function mutations have been reported for GLUL. Overexpression in some cancers may be due to transcriptional regulation rather than activating mutations.
Dominant Negative (DN)
No dominant-negative mutations have been documented for GLUL. The disease is inherited in an autosomal recessive manner, requiring biallelic loss-of-function.
View complete mutation data：
Gene Ontology (GO)
| • glutamate-ammonia ligase activity | • ATP binding |
| • glutamine biosynthetic process | • nitrogen compound metabolic process |
| • response to ammonia | • cellular response to amino acid stimulus |
Pathways
• Alanine
• aspartate and glutamate metabolism (KEGG: hsa00250)
• Arginine biosynthesis (KEGG: hsa00220)
• Nitrogen metabolism (KEGG: hsa00910)
• Glutamine/glutamate metabolism (Reactome: R-HSA-210455)
Protein Summary
The GLUL protein (UniProt P15104) is a 373-amino-acid enzyme that forms a homooctamer. It catalyzes the ATP-dependent condensation of glutamate and ammonia to glutamine. The enzyme is localized in the cytoplasm and mitochondria in some tissues. It plays a critical role in ammonia detoxification, amino acid homeostasis, and neurotransmitter cycling. Post-translational modifications include acetylation and ubiquitination, which regulate its stability and activity. The protein is highly expressed in liver, brain, and kidneys, and its deficiency leads to severe metabolic and neurological disorders.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GLUL Knockout HEK293 Cell Line | EDJ-KQ17879 | Human | 2752 | Details Get a Quote |
| Glul Knockout CHO-K1 Cell Line | EDC90793 | Chinese hamster | 100764163 | Details Get a Quote |
| GLUL Knockout A-549 Cell Line | EDJ-KQ43279 | Human | 2752 | Details Get a Quote |
| GLUL Knockout HCT 116 Cell Line | EDJ-KQ43280 | Human | 2752 | Details Get a Quote |
| GLUL Knockout HeLa Cell Line | EDJ-KQ43281 | Human | 2752 | Details Get a Quote |
| GLUL Knockout Hep-G2 Cell Line | EDJ-KZ267 | Human | 2752 | Details Get a Quote |
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