Further characterization of glutaminase
isozymes from Pseudomonas aeruginosa.
inhibitors target a chemical process called glutaminolysis, in which the amino acid glutamine is broken down, releasing energy that cancer cells use to grow.
[alpha]KG: [alpha]-ketoglutarate; D-Ser: D-Serine; GS: glutamine synthase; EAAT: excitatory amino acid transporter; EETs: epoxyeicosatrienoic acids; Glut-: glutamate; Gln: glutamine; GLS: glutaminase
; mGluRI: group I metabotropic glutamate receptors; PG: prostaglandins; Pyr: pyruvate; TCA: tricarboxylic acid cycle.
GLS, the enzyme catalyzing the conversion of glutamine to GLU, which can enter the mitochondrion and the TCA cycle, represents a possible drug target since glutaminase
inhibitors are available and are tested in clinical trials .
CB-839 is an investigational orally administered glutaminase
inhibitor currently in Phase 1/2 clinical studies.
The key stemness genes glutaminase
2 (GLS2), cystathionine-beta-synthase (CBS), and cystathionine gamma-lyase (CTH) were enriched in CTC-MCC-41, whereas CD200 molecule (CD200), spalt like transcription factor 4 (SALL4), and inhibitor of DNA binding 1 (ID1) were over-represented in HT-29.
Activation of PPAR[alpha] suppresses anaplerosis from glutamine, by repressing the expression of glutaminase
and glutamate dehydrogenase, thus potentially counteracting c-myc-dependent activation of glutaminolysis in tumor .
This induced the upregulation of GLS2 (Glutaminase
2), one of the miR-16 targets, which enhanced glutamine uptake and the rate of glutaminolysis, which is known to increase in cancer cells.
GA: [GABA.sub.A] receptors, GB: [GABA.sub.B] receptors, GAD: glutamate decarboxylase, A: AMPA receptors, N: NMDA receptors, M: metabotropic glutamate receptors, EAAT: excitatory amino acid transporters, blue dots: GABA, red dots: glutamate, Glu: glutamate, Gln: glutamine, GS: glutamine synthetase, GT: glutaminase
, VGlut: vesicular glutamate transporter proteins, and (-): inhibitory effects.
Based on metabolomic and protein expression data, proteins involved in the lactate production (LDH-A), serine and one carbon metabolism (phosphoglycerate dehydrogenase and serine hydroxymethyltransferase 2), glutaminolysis (glutaminase
), and fatty acid biosynthesis (fatty acid synthase), have been proposed for cancer therapy  and may also represent attractive therapeutic targets in TC.
In macrophages and microglia in active MS lesions, glutaminase
, the enzyme that produces glutamate, reveals increased immunoreactivity .
To facilitate this cycle, neurons possess high levels of two glutaminase
genes, GLS1 and GLS2 (phosphate-activated mitochondrial glutaminase
), to function in the breakdown of glutamine to glutamate, a process that releases ammonia, but small amounts of glutaminase
(mostly GLS1) have also been localized to astrocytes .