ArticleThe Journal of biological chemistry2013
Active glutaminase C self-assembles into a supratetrameric oligomer that can be disrupted by an allosteric inhibitor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed, 88 citations in OpenAlex.
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- HIF2α inhibits glutaminase clustering in mitochondria to sustain growth of clear cell renal cell carcinoma.JCI insight · 2025Article
- Recent insights into the roles and therapeutic potentials of GLS1 in inflammatory diseases.Journal of pharmaceutical analysis · 2025Review
- Structure and enzymology of glutaminase mutants that disrupt glutamine-glutamate homeostasis and cause neurological disease.bioRxiv : the preprint server for biology · 2025Article
- AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.Cell research · 2024Article
- Emerging roles of the chromatin remodeler MORC2 in cancer metabolism.Medical oncology (Northwood, London, England) · 2024Review
- HuR controls glutaminase RNA metabolism.Nature communications · 2024Article
- Filament formation drives catalysis by glutaminase enzymes important in cancer progression.Nature communications · 2024Article
- Structural basis for activation and filamentation of glutaminase.Cell research · 2024Article
- Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.Frontiers in pharmacology · 2024Review
- Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.Nature structural & molecular biology · 2023Article
- Agglomeration: when folded proteins clump together.Biophysical reviews · 2023Review
- Regulation of tumor metabolism by post translational modifications on metabolic enzymes.Cancer gene therapy · 2023Review
- Alone and together: current approaches to targeting glutaminase enzymes as part of anti-cancer therapies.Future drug discovery · 2023Review
- Hormone-Glutamine Metabolism: A Critical Regulatory Axis in Endocrine-Related Cancers.International journal of molecular sciences · 2022Review
- Article
- Phylogenies from unaligned proteomes using sequence environments of amino acid residues.Scientific reports · 2022Article
- Structural basis for the helical filament formation of Escherichia coli glutamine synthetase.Protein science : a publication of the Protein Society · 2022Article
- Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates.Scientific reports · 2022Article
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Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The phosphate-dependent transition between enzymatically inert dimers into catalytically capable tetramers has long been the accepted mechanism for the glutaminase activation. Here, we demonstrate that activated glutaminase C (GAC) self-assembles into a helical, fiber-like double-stranded oligomer and propose a molecular model consisting of seven tetramer copies per turn per strand interacting via the N-terminal domains. The loop (321)LRFNKL(326) is projected as the major regulating element for self-assembly and enzyme activation. Furthermore, the previously identified in vivo lysine acetylation (Lys(311) in humans, Lys(316) in mouse) is here proposed as an important down-regulator of superoligomer assembly and protein activation. Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, a known glutaminase inhibitor, completely disrupted the higher order oligomer, explaining its allosteric mechanism of inhibition via tetramer stabilization. A direct correlation between the tendency to self-assemble and the activity levels of the three mammalian glutaminase isozymes was established, with GAC being the most active enzyme while forming the longest structures. Lastly, the ectopic expression of a fiber-prone superactive GAC mutant in MDA-MB 231 cancer cells provided considerable proliferative advantages to transformed cells. These findings yield unique implications for the development of GAC-oriented therapeutics targeting tumor metabolism.
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