ArticleBiochimie2021
Structure and activation mechanism of the human liver-type glutaminase GLS2.
Article in Biochimie, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease.The Journal of biological chemistry · 2026Article
- Targeting the mitochondrial thermogenesis pathway for neuroprotection in neonatal hypoxic-ischemic encephalopathy by curcumin.Acta pharmacologica Sinica · 2026Article
- Glutamine metabolic enzymes: to filament or not to filament?Biochemical Society transactions · 2026Review
- Structural reassignment of compound 968, an allosteric glutaminase inhibitor.Beilstein journal of organic chemistry · 2026Article
- Article
- Structure and enzymology of glutaminase mutants that disrupt glutamine-glutamate homeostasis and cause neurological disease.bioRxiv : the preprint server for biology · 2025Article
- Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Revealing the Transcriptional and Metabolic Characteristics of Sebocytes Based on the Donkey Cell Transcriptome Atlas.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- GLS2 reduces the occurrence of epilepsy by affecting mitophagy function in mouse hippocampal neurons.CNS neuroscience & therapeutics · 2024Article
- Filament formation drives catalysis by glutaminase enzymes important in cancer progression.Nature communications · 2024Article
- Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.Nature structural & molecular biology · 2023Article
- Two Faces of Glutaminase GLS2 in Carcinogenesis.Cancers · 2023Review
- Review
- Alone and together: current approaches to targeting glutaminase enzymes as part of anti-cancer therapies.Future drug discovery · 2023Review
- Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae.Heliyon · 2022Review
- The Role of Methionine Residues in the Regulation of Liquid-Liquid Phase Separation.Biomolecules · 2021Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancer cells exhibit an altered metabolic phenotype, consuming higher levels of the amino acid glutamine. This metabolic reprogramming depends on increased mitochondrial glutaminase activity to convert glutamine to glutamate, an essential precursor for bioenergetic and biosynthetic processes in cells. Mammals encode the kidney-type (GLS) and liver-type (GLS2) glutaminase isozymes. GLS is overexpressed in cancer and associated with enhanced malignancy. On the other hand, GLS2 is either a tumor suppressor or an oncogene, depending on the tumor type. The GLS structure and activation mechanism are well known, while the structural determinants for GLS2 activation remain elusive. Here, we describe the structure of the human glutaminase domain of GLS2, followed by the functional characterization of the residues critical for its activity. Increasing concentrations of GLS2 lead to tetramer stabilization, a process enhanced by phosphate. In GLS2, the so-called "lid loop" is in a rigid open conformation, which may be related to its higher affinity for phosphate and lower affinity for glutamine; hence, it has lower glutaminase activity than GLS. The lower affinity of GLS2 for glutamine is also related to its less electropositive catalytic site than GLS, as indicated by a Thr225Lys substitution within the catalytic site decreasing the GLS2 glutamine concentration corresponding to half-maximal velocity (K
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