Glutaminase (GLS)

Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the hydrolysis of glutamine into glutamate and ammonia, serving as the first and rate-limiting step in glutaminolysis. In many high-grade tumors, oncogenic drivers like MYC induce a state of 'glutamine addiction,' where cancer cells rely on this pathway to replenish TCA cycle intermediates (anaplerosis) and provide nitrogen for nucleotide and amino acid biosynthesis. By supporting the production of glutathione, GLS also plays a critical role in maintaining redox balance and protecting cancer cells from oxidative stress. Therapeutic strategies focus on small-molecule allosteric inhibitors, such as telaglenastat, which aim to disrupt tumor metabolism and sensitize cells to other treatments like chemotherapy or immunotherapy. While clinically promising, targeting GLS requires careful consideration of its role in normal tissues and the immune microenvironment, particularly its necessity for effector T-cell function.

Other names

GLS1GLS2Kidney-type glutaminaseLiver-type glutaminaseL-glutamine amidohydrolasePhosphate-activated glutaminase

Allosteric inhibition of the glutaminase enzyme, which prevents the conversion of glutamine to glutamate and ammonia, thereby starving cancer cells of essential carbon and nitrogen sources for the TCA cycle and nucleotide biosynthesis.