Category: catabolism
Distinct from glutamate_glutamine_cycle (the CNS astrocyte-neuron shuttle). This pathway covers the **glutaminolysis arm**: glutamine → glutamate → α-ketoglutarate → TCA cycle, which fuels biosynthetic precursors + NADPH in rapidly-proliferating cells. Step 1: glutamine import via SLC1A5 (ASCT2) — proliferating cells (cancer, activated T-cells) massively upregulate ASCT2; clinical drug target. Step 2: glutamine → glutamate + NH₃ via glutaminase (GLS1/GLS2) — GLS1 is the canonical cancer-cell isoform (Myc-driven), GLS2 is the p53-driven tumor-suppressor isoform; GLS1 inhibitors (telaglenastat / CB-839) in oncology trials. Step 3: glutamate → α-ketoglutarate via glutamate dehydrogenase (GDH) or via transamination (AST, ALT) — generates α-KG that enters TCA. Step 4: α-KG → succinate → fumarate → malate → OAA cycles through the TCA, providing citrate for fatty acid synthesis + NADPH for biosynthesis ("reductive carboxylation" of α-KG → citrate is glutamine-dependent in hypoxia). Step 5: glutamine also donates nitrogen for purine + pyrimidine + hexosamine synthesis (GFAT enzyme — HBP pathway). Therapeutic significance: cancer cells become "glutamine-addicted" once they switch from oxidative phosphorylation to Warburg-like metabolism + need glutamine to sustain TCA anaplerosis (this is the basis for GLS1 inhibitor oncology trials). Conditionally-essential amino acid in critical illness + post-surgery + cachexia. Cross-links: [[glutamate_glutamine_cycle]], [[tca_cycle]], [[purine_de_novo_synthesis]], [[pyrimidine_metabolism]] (glutamine donates N for pyrimidine ring), [[mtor_signaling]] (glutamine activates mTORC1 via Rag GTPases).