Glutaminase 1 (GLS1) (GLS1)

Glutaminase 1 (GLS1) is a mitochondrial enzyme that catalyzes the hydrolysis of L-glutamine to L-glutamate and ammonia, representing the initial and rate-limiting step of glutaminolysis [1]. In humans, the GLS gene undergoes alternative splicing to produce two distinct isoforms: the kidney-type glutaminase (KGA) and the more enzymatically potent glutaminase C (GAC) [2]. This enzyme is frequently upregulated in various cancers, often under the control of the MYC oncogene, to meet the increased metabolic demands of rapid cell proliferation [3]. By providing glutamate, GLS1 fuels the tricarboxylic acid (TCA) cycle through anaplerosis and supports the production of glutathione, which is critical for maintaining cellular redox balance and surviving oxidative stress [4]. Therapeutic targeting of GLS1 primarily involves small-molecule allosteric inhibitors, such as telaglenastat (CB-839), which bind to the enzyme's regulatory site to prevent the formation of its active tetrameric state [5]. While promising for oncology, the role of GLS1 in producing glutamate—a major excitatory neurotransmitter—raises potential concerns regarding neurotoxicity and other off-target effects in the central nervous system [6].

Other names

Kidney-type glutaminaseK-type glutaminaseGlutaminase CGACKGAL-glutamine amidohydrolaseGLSGLS1

Allosteric inhibition of the GLS1 enzyme, preventing the formation of the active tetrameric state and thereby blocking the conversion of glutamine to glutamate [5].