Figure 1.

Metabolic fates of glutamine within the tumor cell. The amide nitrogen of glutamine can be utilized by enzymes in pyrimidine and purine nucleotide synthesis. Additionally, glutamine itself is utilized by glutamine-fructose amidotransferase 1/2 (GFAT1/2) to begin the hexosamine biosynthesis pathway (HBP). Glutamine-derived glutamate is utilized in the synthesis of glutathione (GSH) by the subsequent activities of GCL (glutamine-cysteine ligase) and GS (glutathione synthetase). Glutamine is converted to glutamate by the action of glutaminase (GLS) and can be used in the synthesis of alanine or converted to α-KG (alpha-ketoglutarate). Glutamate-derived α-KG can be used as a direct substate for epigenetic modifcation by histone demethylases, as anaplerotic replenishment of the tricarboxylic acid cycle (TCA cycle) intermediates depleted by other biosynthetic reactions, or used for fatty acid synthesis via conversion to citrate in the process of reductive carboxylation (dashed arrows). Oxaloacetate (OAA) can additionally be used to synthesise aspartate and asparagine. Glucose-derived pyruvate (Pyr) and acetyl-CoA (Ac-CoA) continue to contribute to the TCA cycle under these anaplerotic conditions.