Glutamine Metabolism in Cancer Biology

Glutamine serves as a pivotal nutrient in cancer cell metabolism, supplying both carbon and nitrogen required for biosynthetic and bioenergetic processes. Tumour cells often exhibit ‘glutamine addiction’, characterised by a heightened dependence on exogenous glutamine to fuel the tricarboxylic acid (TCA) cycle via anaplerosis, to support nucleotide and amino acid synthesis, and to maintain redox balance. Key enzymes such as glutaminase catalyse the conversion of glutamine to glutamate, which is further metabolised to 2-ketoglutarate, feeding into the TCA cycle. Recent advances reveal that dynamic regulation of glutamine metabolism occurs through structural assemblies of metabolic enzymes, adaptive responses to nutrient stress, and interactions with the tumour microenvironment. Dysregulation of glutamine uptake transporters, such as ASCT2, and modulation of ancillary pathways, including the malate shuttle and urea cycle, contribute to tumour proliferation, survival under hypoxia, and metastatic potential. Exploiting these metabolic vulnerabilities has emerged as a promising strategy for targeted therapy and for enhancing anticancer immunity.

Research from Nature Portfolio

Filamentous assemblies of the glutaminase isoforms GAC and GLS2 have been shown to be integral to their catalytic activation. High-resolution cryo-EM structures reveal that filament formation positions an activation loop and lid domain to facilitate glutamine binding and hydrolysis, highlighting new allosteric sites for drug targeting. Investigations into T cell metabolism demonstrate that the malate shuttle enzyme GOT1 sustains glutaminolysis in CD8+ T cells by producing 2-ketoglutarate, which detoxifies ammonia and prevents metabolic collapse during chronic antigen exposure. This mechanism underscores the importance of maintaining ammonia-neutral pathways for sustained immune surveillance in tumours. Foundational proteomic analyses have identified a shift in glutamine nitrogen partitioning from TCA cycle anaplerosis towards nucleotide biosynthesis as malignant progression advances. This metabolic rewiring, governed by the relative activities of glutaminase and nucleotide biosynthetic enzymes, supports rapid proliferation and presents potential metabolic biomarkers for aggressive cancer subtypes.

Glutamine Metabolism in Cancer Biology publication trend

The graph below shows the total number of articles in glutamine metabolism in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Glutaminolysis: Catabolic pathway converting glutamine to glutamate and downstream metabolites for energy and biosynthesis.

Glutaminase (GLS): Mitochondrial enzyme that hydrolyses glutamine into glutamate, initiating glutaminolysis.

Anaplerosis: Replenishment of TCA cycle intermediates to sustain mitochondrial energy production.

2-Ketoglutarate (2-KG): TCA cycle intermediate derived from glutamate, essential for biosynthesis and redox balance.

ASCT2 (SLC1A5): Sodium-dependent glutamine transporter frequently upregulated in cancer cells.

Malate shuttle: Biochemical mechanism transferring reducing equivalents between cytosol and mitochondria.

Filament formation: Polymerisation of metabolic enzymes into filamentous structures regulating their catalytic activity.

References

1. Filament formation drives catalysis by glutaminase enzymes important in cancer progression. Nature Communications (2024).
2. The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. Nature Immunology (2023).
3. A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer. Nature Communications (2020).
4. Crosstalk between metabolism and cell death in tumorigenesis. Molecular Cancer (2024).
5. Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level. Advanced Science (2024).
6. Targeting ASCT2‐mediated glutamine uptake blocks prostate cancer growth and tumour development. The Journal of Pathology (2015).