{"entity":{"id":"glutamine-metabolism","kind":"pathway","name":"Glutamine addiction","aka":[],"tldr":"After glucose, glutamine is the tumour's favourite food. It feeds the energy cycle, donates nitrogen for making DNA letters, and makes the antioxidant glutathione. MYC- and KRAS-driven cancers eat so much of it that they starve the T cells next door.","summary":"Glutamine enters via SLC1A5 (ASCT2) and SLC38A2; glutaminase (GLS, MYC-induced via miR-23 suppression; GLS2 is p53-induced) converts it to glutamate, which GLUD1 or transaminases (GOT1/2, GPT2) convert to α-ketoglutarate for TCA anaplerosis, supporting oxidative phosphorylation and, under hypoxia or IDH mutation, reductive carboxylation to citrate for lipids. Glutamine's amide nitrogen feeds purine and pyrimidine synthesis (CAD, PPAT) and hexosamines; glutamate makes glutathione (with cysteine via SLC7A11) and aspartate (KRAS-mutant pancreatic cancer routes glutamine through GOT1 to maintain NADPH). mTORC1 senses glutamine-derived α-KG. Tumour uptake depletes glutamine in the microenvironment, impairing T-cell effector function. Drugs: the glutaminase inhibitor telaglenastat (CB-839) failed in RCC (CANTATA) and was inactive in KEAP1-mutant NSCLC (KEAPSAKE); the broad glutamine antagonist prodrug DRP-104 (sirpiglenastat) and ASCT2 inhibitors are in early trials; asparaginase (which also depletes glutamine) is standard in ALL. Glutamine PET tracers (18F-FGln) image glioma where FDG fails.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Glutaminolysis","links":[{"label":"Altman, Stine & Dang, From Krebs to clinic: glutamine metabolism to cancer therapy (Nat Rev Cancer 2016)","url":"https://doi.org/10.1038/nrc.2016.71"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["all-leukemia","rcc","pancreatic","glioblastoma"],"sections":[],"technologies":["metabolic-therapy","fdg-pet","pet"],"targets":["kras","idh","akt","pd1"],"drugs":["asparaginase","ivosidenib","vorasidenib"],"companies":[],"institutions":[],"pathways":["cancer-metabolism","myc","ras-mapk","keap1-nrf2","nutrient-competition-tme"],"terms":["warburg-effect","deregulating-cellular-energetics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-altman-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A construction site that runs on two deliveries: sand (glucose) for bulk and steel (glutamine) for the frame and the rebar. MYC doubles the steel order. Cutting one delivery rarely stops the build because the site switches suppliers; that is why single metabolic drugs have disappointed.","nodes":[{"id":"gln","label":"Glutamine (SLC1A5)","x":12,"y":30},{"id":"gls","label":"Glutaminase (GLS)","x":40,"y":30},{"id":"glu","label":"Glutamate","x":66,"y":30},{"id":"akg","label":"α-KG → TCA anaplerosis","x":66,"y":60},{"id":"gsh","label":"Glutathione, NADPH","x":90,"y":45},{"id":"nuc","label":"Nucleotides (N donor)","x":40,"y":8},{"id":"myc","label":"MYC, KRAS drive uptake","x":12,"y":65,"targetId":"kras"},{"id":"idh","label":"IDH → 2-HG / reductive","x":90,"y":80,"targetId":"idh"},{"id":"tcell","label":"T cells starved","x":40,"y":85,"targetId":"pd1"},{"id":"mtor","label":"mTORC1 sensing","x":12,"y":92,"targetId":"akt"}],"edges":[{"from":"gln","to":"gls","type":"activates"},{"from":"gls","to":"glu","type":"activates"},{"from":"gln","to":"nuc","type":"activates"},{"from":"glu","to":"akg","type":"activates"},{"from":"glu","to":"gsh","type":"activates"},{"from":"akg","to":"idh","type":"activates"},{"from":"myc","to":"gls","type":"activates"},{"from":"myc","to":"gln","type":"activates"},{"from":"gln","to":"tcell","type":"inhibits"},{"from":"akg","to":"mtor","type":"activates"}],"interventions":["Asparaginase (depletes asparagine and glutamine) in ALL","Glutaminase inhibitor telaglenastat: negative in RCC and NSCLC; glutamine antagonist DRP-104 and ASCT2 blockers in early trials","IDH inhibitors (ivosidenib, vorasidenib) block the oncometabolite branch","Glutamine PET (18F-FGln) for glioma; metabolic imaging to pick fuel-dependent tumours"]},"route":"/pathways/glutamine-metabolism/","neighbours":{"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"}],"technology":[{"id":"fdg-pet","kind":"technology","name":"FDG PET","route":"/technologies/fdg-pet/"},{"id":"metabolic-therapy","kind":"technology","name":"Metabolic therapy: starving the tumour of a nutrient","route":"/technologies/metabolic-therapy/"},{"id":"pet","kind":"technology","name":"PET (positron emission tomography)","route":"/technologies/pet/"}],"target":[{"id":"akt","kind":"target","name":"AKT","route":"/targets/akt/"},{"id":"idh","kind":"target","name":"IDH1 / IDH2","route":"/targets/idh/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"asparaginase","kind":"drug","name":"Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)","route":"/drugs/asparaginase/"},{"id":"ivosidenib","kind":"drug","name":"Ivosidenib","route":"/drugs/ivosidenib/"},{"id":"vorasidenib","kind":"drug","name":"Vorasidenib","route":"/drugs/vorasidenib/"}],"pathway":[{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/"},{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","route":"/pathways/keap1-nrf2/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"nutrient-competition-tme","kind":"pathway","name":"Nutrient competition & metabolic immunosuppression","route":"/pathways/nutrient-competition-tme/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"deregulating-cellular-energetics","kind":"term","name":"Hallmark: reprogramming cellular metabolism","route":"/terms/deregulating-cellular-energetics/"},{"id":"metabolic-theory-of-cancer","kind":"term","name":"Metabolic theory of cancer: from Warburg to oncometabolites","route":"/terms/metabolic-theory-of-cancer/"},{"id":"warburg-effect","kind":"term","name":"Warburg effect","route":"/terms/warburg-effect/"}],"paper":[{"id":"paper-altman-nat-rev-cancer","kind":"paper","name":"From Krebs to clinic: glutamine metabolism to cancer therapy","route":"/key-papers/paper-altman-nat-rev-cancer/"}]}}