Glutamine is an important metabolic fuel that helps rapidly proliferating cells meet the increased demand for ATP, biosynthetic precursors, and reducing agents. Glutamine enters the cell through the amino acid transporter, ASCT2/SLC1A5, and is converted to glutamate in the mitochondria through a deamination reaction catalyzed by glutaminase (GLS). Glutamate is converted to the TCA cycle intermediate α-ketoglutarate (α-KG) by either glutamate dehydrogenase (GDH) or by the alanine or aspartate transaminases (TAs), which produce their corresponding amino acid in addition to α-KG. α-KG is a critical metabolite that serves in both ATP production and in replenishing TCA cycle intermediates, a process termed anaplerosis. During periods of hypoxia or mitochondrial dysfunction, α-KG can be converted to citrate in a reductive carboxylation reaction catalyzed by IDH2. The newly formed citrate exits the mitochondria where it is used to synthesize fatty acids and amino acids and produce the reducing agent, NADPH (cataplerosis). In the cytosol, glutamine donates its γ (amide) nitrogen for the synthesis of nucleotides and hexosamines, producing glutamate in the process. Cytosolic glutamate is critical for maintaining redox homeostasis and protecting cells against oxidative stress through the production of glutathione (GSH). Many cancer cells display oncogene-dependent addictions to glutamine, and glutamine itself can promote proliferative signaling. For example, glutamine influx via SLC1A5 is coupled to its efflux through the SLC7A5/LAT1 transporter, allowing leucine to enter the cell and triggering mTORC1-mediated cell growth. In addition, the signaling molecules Akt, Ras, and AMPK activate glycolytic enzymes and induce lactate production (Warburg effect), causing cancer cells to require glutamine metabolism to meet increased energy demands. The proto-oncogene, c-Myc, upregulates glutaminolysis through transcriptional activation of GLS and the SLC1A5 genes. Glutamine-mediated glycosylation of proteins, including growth factor receptors, can target proteins to the cell surface, inducing their activation.
