ArticleProceedings of the National Academy of Sciences of the United States of America2012
Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 177 papers, 1 of them a synthesis that pooled it.
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Who cites it
177 citing papers in PubMed, 1 synthesis or guideline pooled it, 280 citations in OpenAlex.
- The role of glutamate receptors in the regulation of the tumor microenvironment.Frontiers in immunology · 2023Pooled it
- Trial
- Review
- Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease.The Journal of biological chemistry · 2026Article
- Regulation of gene expression by alternative polyadenylation in health and disease.Nature reviews. Genetics · 2026Review
- Glutamine metabolic enzymes: to filament or not to filament?Biochemical Society transactions · 2026Review
- Mediterranean Pattern Diet in Multiple Sclerosis: A Review Focusing on Immunometabolites.Current neuropharmacology · 2026Review
- WTAP-Mediated Glutaminase Splicing Bias Suppresses Ferroptosis in Hepatocellular Carcinoma.Cancer communications (London, England) · 2026Article
- Expression of Glutamatergic Signaling in Canine Oral Melanocytic Neoplasms.Veterinary sciences · 2025Article
- Recent insights into the roles and therapeutic potentials of GLS1 in inflammatory diseases.Journal of pharmaceutical analysis · 2025Review
- The neuro-immune axis in cancer: from mechanisms to therapeutic opportunities.Journal of hematology & oncology · 2025Review
- Reduced Usage ofPhenomics (Cham, Switzerland) · 2025Article
- Structure and enzymology of glutaminase mutants that disrupt glutamine-glutamate homeostasis and cause neurological disease.bioRxiv : the preprint server for biology · 2025Article
- Exploring the role of ferroptosis in esophageal cancer: mechanisms and therapeutic implications.Cell death discovery · 2025Review
- Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.International journal of molecular sciences · 2025Article
- Imaging the uptake and metabolism of glutamine in prostate tumor models using CEST MRI.Npj imaging · 2025Article
- Development of a cuproptosis-related prognostic signature to reveal heterogeneity of the immune microenvironment and drug sensitivity in acute lymphoblastic leukemia.European journal of medical research · 2025Article
- O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma.Cell death discovery · 2025Article
- Stress-induced extracellular vesicles: insight into their altered proteomic composition and probable physiological role in cancer.Molecular and cellular biochemistry · 2025Review
- SLC1A5 is a key regulator of glutamine metabolism and a prognostic marker for aggressive luminal breast cancer.Scientific reports · 2025Article
117 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutamine is an essential nutrient for cancer cell proliferation, especially in the context of citric acid cycle anaplerosis. In this manuscript we present results that collectively demonstrate that, of the three major mammalian glutaminases identified to date, the lesser studied splice variant of the gene gls, known as Glutaminase C (GAC), is important for tumor metabolism. We show that, although levels of both the kidney-type isoforms are elevated in tumor vs. normal tissues, GAC is distinctly mitochondrial. GAC is also most responsive to the activator inorganic phosphate, the content of which is supposedly higher in mitochondria subject to hypoxia. Analysis of X-ray crystal structures of GAC in different bound states suggests a mechanism that introduces the tetramerization-induced lifting of a "gating loop" as essential for the phosphate-dependent activation process. Surprisingly, phosphate binds inside the catalytic pocket rather than at the oligomerization interface. Phosphate also mediates substrate entry by competing with glutamate. A greater tendency to oligomerize differentiates GAC from its alternatively spliced isoform and the cycling of phosphate in and out of the active site distinguishes it from the liver-type isozyme, which is known to be less dependent on this ion.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.