Glutaminase liver isoform, mitochondrial (GLS2)

Glutaminase liver isoform, mitochondrial (GLS2), is a mitochondrial enzyme encoded by the GLS2 gene on chromosome 12q13.3. It catalyzes the hydrolysis of L-glutamine to L-glutamate and ammonia, serving a pivotal role in glutamine metabolism and mitochondrial energy production[1][2]. GLS2 is a member of the glutaminase family, sharing significant sequence similarity with kidney-type glutaminase (GLS), but differing in tissue distribution, kinetic properties, and sensitivity to known inhibitors. While classically considered liver-specific, GLS2 is found in other tissues and exists in multiple isoforms, notably LGA and GAB, via alternative splicing[3]. Biologically, GLS2 can act as either a tumor suppressor (e.g., hepatocellular carcinoma) or an oncogene (e.g., breast cancer, MYCN-amplified neuroblastoma), highlighting its context-dependent role in cancer biology[1][3][4]. Mechanistically, its activity is tightly regulated through tetramerization, phosphate activation, and key conformational changes in its catalytic and regulatory loops. Unlike GLS, GLS2 is resistant to classical GLS inhibitors (BPTES, CB-839) due to differences in its activation loop[2]. No direct clinically approved drugs specifically target GLS2, but it is a candidate for drug development in metabolic cancer therapy and as a disease biomarker in certain cancer subtypes[1][2][3].

Other names

Glutaminase 2liver-type glutaminaseLGAhLGAGlutaminase IPhosphate-activated glutaminasePhosphate-dependent glutaminaseL-glutaminaseL-glutamine amidohydrolasebreast cell glutaminasemitochondrial glutaminaseGABGlutaminase 2 (GLS2)

Inhibitors of glutaminase activity reduce glutamate production from glutamine, impacting metabolic support of rapidly proliferating tumor cells and altering redox homeostasis[2][3].