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).
Organ Systems
immune-hematologic
digestive
Pathway Steps
extracellular glutamine → cytoplasmic glutamine — via SLC1A5 (ASCT2) — upregulated in cancer + activated T-cells. Glutamine is the most abundant blood amino acid, and many proliferating cells are “glutamine-addicted”, importing it via transporters such as ASCT2/SLC1A5. This MYC-driven uptake is often rate-limiting — which is why ASCT2 inhibition starves glutamine-dependent tumors and is being pursued therapeutically.
glutamine → glutamate + NH₃ — via glutaminase (GLS1 cancer isoform, GLS2 tumor-suppressor isoform); CB-839 inhibitor target. The committed step is deamidation by glutaminase (GLS) to glutamate plus ammonia. GLS is transcriptionally driven by MYC and is the principal anticancer target of this pathway — the inhibitor CB-839 (telaglenastat) blocks it. The released ammonia can itself act as an autophagy and signaling cue.
glutamate → α-ketoglutarate + NH₃ — via glutamate dehydrogenase (GDH) — oxidative deamination. Glutamate is oxidatively deaminated to α-ketoglutarate by glutamate dehydrogenase, releasing a second ammonia and generating NAD(P)H. This route dominates when amino-nitrogen is to be disposed of, linking glutamine catabolism to cellular redox balance and nitrogen economy.
glutamate → α-ketoglutarate + amino-acceptor — via AST / ALT transamination — generates aspartate + alanine respectively. Alternatively, transaminases convert glutamate to α-ketoglutarate while transferring its amino group to a keto-acid acceptor (making alanine or aspartate). This route lets the carbon enter the TCA cycle while the nitrogen is exported into other amino acids — the biosynthetic, rather than disposal, mode.
α-ketoglutarate → TCA-derived citrate (lipid synthesis precursor) — via reductive carboxylation pathway — glutamine-dependent under hypoxia. α-Ketoglutarate is the key anaplerotic input that refills the TCA cycle, replacing intermediates siphoned for biosynthesis. Its citrate can be exported and cleaved to acetyl-CoA for fatty-acid synthesis — and under hypoxia α-KG runs the cycle in reverse (reductive carboxylation) to make lipids, a hallmark of cancer metabolism.
glutamine → glucosamine-6-phosphate — via GFAT — hexosamine biosynthesis pathway (HBP); N donor for protein glycosylation. Glutamine also feeds the hexosamine biosynthesis pathway: its amide nitrogen is donated (by GFAT) to make glucosamine-6-phosphate, precursor of UDP-GlcNAc. This couples nutrient availability to protein glycosylation and O-GlcNAc signaling — a sensor linking metabolism to growth-factor signaling.
glutamine → purine + pyrimidine N donor — via PRPP amidotransferase + CAD enzyme — nucleotide synthesis. Beyond energy, glutamine is a major nitrogen donor for nucleotide synthesis, contributing amide nitrogen to both the purine and pyrimidine rings. This biosynthetic demand is why rapidly dividing cells need so much glutamine — to build DNA/RNA, not merely to make ATP.
Known Modulators
glutamine (substrate) — pathway substrate — clinical use in critical illness, athletic supplementation, GI integrity
l glutamine (substrate) — L-form supplement. conditionally essential in catabolic states
glutamate (substrate) — glutaminase product / downstream pool