Figure 2. Major metabolic and biosynthetic fates of glutamine.

Glutamine enters the mammalian cell through transporters such as SLC1A5 (also known as ASCT2) ¹⁵. Glutamine itself can contribute to nucleotide biosynthesis and uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis for support of protein folding and trafficking ²¹⁰, or is converted to glutamate by glutaminase (GLS or GLS2) ²⁸. Glutamate can contribute to the synthesis of glutathione ¹¹⁰, and has many other metabolic fates in the cell that impact on several inborn errors of metabolism, which were recently reviewed ²¹¹. Glutamate is converted to α-ketoglutarate (αKG) through one of two sets of enzymes, glutamate dehydrogenase (GLUD1 or GLUD2, henceforth referred to collectively as GLUD) or aminotransferases ³⁰. While the byproduct of GLUD is NH₄⁺, the byproduct of aminotransferase reactions is other amino acids. Note that aminotransferases may be present either in the cytoplasm or the mitochondria. α-ketoglutarate enters the tricarboxylic acid (TCA) cycle and can provide energy for the cell. Malate exiting the TCA cycle can produce pyruvate and NADPH for reducing equivalents ³¹, and oxaloacetate (OAA) can be converted to aspartate to support nucleotide synthesis ³⁴. These two pathways are illustrated in more detail in Figure 4. Alternately, α-KG can proceed backwards through the TCA cycle, in a process called reductive carboxylation (RC) to produce citrate, which supports synthesis of acetyl-CoA and lipids ⁸⁷.