{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Feng S"],"funding":["NCI NIH HHS","NIGMS NIH HHS","NIH HHS"],"pubmed_abstract":["The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the 'glutamine addiction' of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide an unprecedented view of the conformational states essential for catalysis. Filament formation guides an 'activation loop' to assume a specific conformation that works together with a 'lid' to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2023.02.16.528860"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9949068"],"repository":["biostudies-literature"],"pubmed_title":["Filament formation drives catalysis by glutaminase enzymes important in cancer progression."],"pmcid":["PMC9949068"],"funding_grant_id":["R35 GM122575","S10 OD030470","R35 GM152206","R01 CA201402","U24 GM129539"],"pubmed_authors":["Cerione RA","Aplin C","Nguyen TT","Feng S","Milano SK"],"additional_accession":[]},"is_claimable":false,"name":"Filament formation drives catalysis by glutaminase enzymes important in cancer progression.","description":"The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the 'glutamine addiction' of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide an unprecedented view of the conformational states essential for catalysis. Filament formation guides an 'activation loop' to assume a specific conformation that works together with a 'lid' to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jul","modification":"2026-06-24T03:09:21.415Z","creation":"2025-02-18T23:45:21.015Z"},"accession":"S-EPMC9949068","cross_references":{"pubmed":["36824706"],"doi":["10.1101/2023.02.16.528860"]}}