Glutaminase 1, commonly referred to as GLS1, is an enzyme present within human cells. Its primary function involves converting glutamine into glutamate. This conversion is a fundamental process, underpinning various cellular activities. GLS1 is found in most tissues and plays a role in regulating acid-base balance in the kidneys and generating glutamate in the brain.
Role in Cellular Energy
GLS1 is involved in glutaminolysis, a biochemical pathway that converts glutamine to glutamate. Glutamine serves as a significant fuel and building block for cells, particularly those that divide rapidly. GLS1 facilitates this initial step, transforming glutamine into glutamate and ammonia.
The glutamate produced by GLS1 can then be further metabolized to enter the Krebs cycle, also known as the tricarboxylic acid (TCA) cycle. This cycle is a central part of cellular respiration, generating adenosine triphosphate (ATP), the primary energy currency of cells. Beyond energy production, glutamate also serves as a precursor for the synthesis of other molecules, including glutathione, which helps cells manage oxidative stress. GLS1 activity is foundational to cellular metabolism, supplying energy and raw materials.
GLS1 and Cancer Development
Cancer cells often exhibit a reprogrammed metabolism, displaying an increased demand for glutamine to support their aggressive growth and proliferation. Many malignant tumor cells show “glutamine addiction.” Elevated GLS1 activity is frequently observed in numerous types of cancer, including breast, lung, prostate, and brain cancers.
Overexpression of GLS1 enables cancer cells to consume large quantities of glutamine, fueling their rapid growth, survival, and biomass production, while generating robust energy. GLS1 activity can also help cancer cells resist cell death and maintain redox balance, which is crucial for coping with the stress of rapid division. Studies indicate that increased GLS1 expression is associated with decreased patient survival in many human cancers, suggesting its role as a prognostic biomarker.
Targeting GLS1 for Therapeutic Purposes
The role of GLS1 in supporting cancer cell metabolism has made it an attractive target for potential cancer treatment strategies. By inhibiting GLS1, researchers aim to disrupt the cancer cells’ glutamine supply, effectively “starving” them and slowing or stopping their growth. This metabolic disruption can lead to programmed cell death or make cancer cells more vulnerable to other treatments.
GLS1 inhibitors are currently under investigation in preclinical and clinical trials. These inhibitors typically work by binding to the enzyme’s active site, disrupting its function. While promising, challenges include ensuring the specificity of these inhibitors to minimize off-target effects and exploring their potential in combination with existing therapies to enhance overall treatment efficacy.