General glutamine-metabolizing enzymes and transporters

General glutamine-metabolizing enzymes and transporters refers to a broad metabolic network essential for cellular nitrogen and carbon homeostasis, rather than a single molecular entity. This system is primarily composed of enzymes like glutaminase (GLS), which converts glutamine into glutamate for use in the tricarboxylic acid (TCA) cycle, and transporters such as SLC1A5 (ASCT2) and SLC7A5 (LAT1) that facilitate the high-rate uptake of glutamine required by rapidly dividing cells [Altman et al., 2016, Nature Reviews Cancer]. In many malignancies, this pathway is pathologically upregulated—a phenomenon known as glutamine addiction—to support bioenergetics, nucleotide biosynthesis, and the maintenance of redox balance through glutathione production [Matés et al., 2019, Archives of Toxicology]. Pharmacological targeting of this network involves various strategies, including the use of small-molecule GLS inhibitors like telaglenastat and transporter antagonists like V-9302, which aim to starve tumors of this critical nutrient [Schulte et al., 2018, Nature Medicine]. However, therapeutic development is complicated by the broad physiological roles of these components, as glutamine is also vital for healthy processes including neurotransmitter synthesis and immune cell proliferation [Yoo et al., 2020, Cancer & Metabolism]. Consequently, clinical applications must balance potent anti-tumor activity with potential toxicities related to neurological and immunological dysfunction.

Other names

Glutaminolysis pathwayGlutamine metabolic networkGlutamine transporters and enzymesGlutamine utilization pathway

Inhibition of glutaminase (GLS1) to block the conversion of glutamine to glutamate; competitive inhibition of solute carrier transporters (e.g., SLC1A5/ASCT2) to prevent cellular glutamine uptake; systemic depletion of glutamine levels to starve glutamine-dependent cells.