glutaminase

Glutaminase is an enzyme that catalyzes the hydrolysis of glutamine to glutamate and ammonium, a key step in glutamine metabolism. The reaction provides substrates for energy production and biosynthetic pathways, and glutamate can serve as a neurotransmitter or a source for α-ketoglutarate in the TCA cycle.

In mammals, there are two main gene families: GLS1, encoding the kidney-type glutaminase with isoforms KGA and GAC produced by alternative splicing, and GLS2, encoding the liver-type enzyme. GLS1 and GLS2 have distinct tissue distributions and regulatory properties; GLS1 is highly expressed in kidney and brain, GLS2 in liver and astrocytes.

Glutaminase activity supports anaplerosis and nitrogen metabolism; in the brain, glutamate functions as a neurotransmitter; in rapidly proliferating cells, glutaminolysis provides carbon and nitrogen for biosynthesis.

Regulation of glutaminase activity is influenced by cellular energy status and phosphate levels, and its expression is modulated by developmental cues and hormonal signals. In cancer, GLS1 expression is often upregulated, driven by oncogenic pathways such as Myc and hypoxia-inducible factors, to sustain glutamine utilization for growth. Therapeutic inhibitors, including CB-839 (telaglenastat), selectively target GLS1 and are under investigation in clinical trials for various tumors.