Glutaminase-1, GAC isoform (GAC) (GAC)

Glutaminase-1 (GLS1) is a mitochondrial enzyme that catalyzes the conversion of glutamine to glutamate, a rate-limiting step in glutaminolysis [1.1.2, 1.4.1]. The GAC (Glutaminase C) isoform is a splice variant of the GLS1 gene that exhibits higher catalytic activity and is predominantly expressed in rapidly proliferating cells, including many types of cancer [1.1.3, 1.3.4]. In the context of the 'Warburg effect' and 'glutamine addiction,' GAC provides glutamate for anaplerosis of the tricarboxylic acid (TCA) cycle and for the synthesis of glutathione, which is essential for maintaining redox homeostasis [1.1.1, 1.1.4]. Beyond its role in oncology, GAC is involved in immune cell activation and neurogenesis, and its dysregulation has been implicated in inflammatory and neurodegenerative diseases [1.2.1, 1.2.2]. Pharmacological targeting of GAC focuses on allosteric inhibitors, such as Telaglenastat (CB-839), which stabilize the inactive dimeric form of the enzyme and prevent its transition into the active tetramer [1.1.2, 1.3.4]. These inhibitors are being investigated in clinical trials for various solid tumors, often as part of combination regimens to overcome metabolic adaptation [1.1.1, 1.5.3].

Other names

Glutaminase CGLS1 GACGLS GACMitochondrial glutaminase CShort transcript isoform of GLS1

Allosteric inhibition of the enzyme, typically by preventing the transition from the inactive dimeric state to the active tetrameric state or by inhibiting filament formation [1.1.2, 1.3.4].