Disease relevance of GLS

• In contrast, after onset of acidosis, the level of GA mRNA initially remains unchanged, is then increased 8-fold between 10 and 16 h, and then decreases slightly [1].
• These data support a possible role for intestinal glutaminase in the pathogenesis of hepatic encephalopathy (HE) and could be a new target for future therapies [2].
• Human cutaneous melanoma expresses a significant phosphate-dependent glutaminase activity: a comparison with the surrounding skin of the same patient [3].
• Upon induction, precursor glutaminase accounts for about 25% of total E. coli protein, whereas a lower amount (12%) was achieved for the putative mature protein [4].
• The first complete sequence of human L-glutaminase was deduced from breast cancer glutaminase cDNA cloned in our laboratory [4].

Psychiatry related information on GLS

• Glutamate-, glutaminase-, and taurine-immunoreactive neurons develop neurofibrillary tangles in Alzheimer's disease [5].
• This is based largely on postmortem evidence indicating reduced binding and uptake of D[3H]aspartate, as well as loss of a number of other putative markers, such as phosphate-activated glutaminase activity, glutamate concentration, and the number of pyramidal cell perikarya, with this latter change correlating with the severity of dementia [6].
• Phosphate-activated glutaminase in relation to Huntington's disease and agonal state [7].

High impact information on GLS

• Selective localization of glutaminase in spinal and sensory nerve cells. A potential marker for glutamate neurotransmission [8].
• Here we report the 3D structure of the PLP synthase complex with substrate glutamine bound as well as those of the individual synthase and glutaminase subunits Pdx1 and Pdx2, respectively [9].
• Mutagenesis permitted identification of the remote glutaminase and synthase catalytic centers and led us to propose a mechanism whereby ammonia shuttles between these active sites through a methionine-rich hydrophobic tunnel [9].
• Active MS lesions showed high-level glutaminase expression in macrophages and microglia in close proximity to dystrophic axons [10].
• Hepatic glutaminase expression: relationship to kidney-type glutaminase and to the urea cycle [11].

Chemical compound and disease context of GLS

• The presence of a kidney-type glutaminase (K(m) of 2-5 mm) indicates a high sensitivity of the melanoma to variations in glutamine plasma levels (0.6 to 1 mm) [3].
• Human ependymoblastoma (NNE), primitive neuroectodermal tumor (YKP), glioblastoma (KYG) and small cell lung carcinoma (GLS) that are all transplantable to nude mice were treated with doxorubicin (8 mg/kg) or radiation (1 Gy) [12].
• The activity of phosphate-activated glutaminase, and to a lesser extent of glutamic acid decarboxylase, was reduced in cases of terminal illness, as compared with cases of sudden death [7].
• In gram-positive bacteria and lower eukaryotes this two-subunit CPS has become dedicated to arginine biosynthesis, while in higher eukaryotes the two subunits fused and subsequently lost the glutaminase activity [13].
• Cortical glutaminase, beta-glucuronidase and glucose utilization in Alzheimer's disease [14].

Biological context of GLS

• The human loci for phosphate-activated glutaminase (GLS) and IL9 have previously been mapped to chromosomes 2 and 5, respectively, by analysis of somatic cell hybrid DNAs [15].
• Glutaminase associates with both PDZ proteins through its C-terminal end; mutagenesis of single amino acids revealed the sequence -ESXV as essential for the interaction [16].
• The overall nucleotide sequence of hGA has a very high degree of identity with that of the rat kidney-type GA cDNA (77.4%) and the known portion of the cDNA that encodes the 5.0-kb porcine GA mRNA (81.1%) [17].
• Results obtained from radiation hybrid mapping experiments assigned the K-glutaminase gene to human Chromosome (Chr) 2, and a second locus for L-glutaminase in Chr 12 was identified [18].
• The kinetics and other properties of phosphate-activated glutaminase have for the first time been studied in the crude mitochondrial fraction (P2 fraction) from human brain [19].

Anatomical context of GLS

• The distribution of human glutaminase expression was also investigated: the L-cDNA probe detected a single band of 2.4 kb in liver, brain, and pancreas, whereas a single transcript of approximately 4.4 kb was detected in kidney, brain, heart, placenta, lung, and pancreas by using the K-cDNA probe [18].
• Phosphate-activated glutaminase is found in mammalian small intestine, brain, and kidney, but not in liver [15].
• Effect of pH and bicarbonate on phosphoenolpyruvate carboxykinase and glutaminase mRNA levels in cultured renal epithelial cells [1].
• Granule localization of glutaminase in human neutrophils and the consequence of glutamine utilization for neutrophil activity [20].
• In the central nervous system (CNS), liver-type glutaminase (LGA) shows a unique nuclear localization suggesting its role in the regulation of transcription rather than in the cellular glutamine metabolism [21].

Associations of GLS with chemical compounds

• The enzyme glutaminase in brain is responsible for the synthesis of neurotransmitter glutamate [16].
• Thus, expression of the isolated hGA cDNA should provide a means to purify large amounts of the mitochondrial glutaminase, a protein that catalyzes a key reaction in the metabolism of glutamine and the synthesis of important excitatory and inhibitory neurotransmitters [17].
• The level of PCK mRNA is increased with increasing glucose concentration from 0 to 40 mM, whereas the level of GA mRNA is maximal between 3 and 5 mM glucose [1].
• The use of actinomycin D to measure the half-lives of PCK and GA mRNAs at pH 7.4 and 6.9 indicates that stabilization may fully account for the induction of GA mRNA and contributes to the inductive effects of decreased pH and/or bicarbonate on PCK mRNA [1].
• Before irradiation, GLS and KYG tumours showed significantly higher rates of 18FDG accumulation compared with NNE tumours (P <0.004 and P <0.001, respectively) [22].

Regulatory relationships of GLS

• METHODS: Fibroblast-like synoviocytes (FLSs) obtained from RA patients were cultured and stimulated by GLS [23].
• Elevation of gamma-glutamyltransferase activity in 293 HEK cells constitutively expressing antisense glutaminase mRNA [24].

Other interactions of GLS

• The C-terminus of human glutaminase L mediates association with PDZ domain-containing proteins [16].
• Increases in jejunal glutaminase (38.2%, P < 0.001) and decreases in glutamine synthetase (41.7%, P < 0.001) activities were observed in response to glutamine-supplemented TPN treatment [25].
• RESULTS: GLS demonstrated a self-induction of mRNA in cultured RA FLSs [23].
• CONCLUSIONS: This IFN-gamma-mediated decrease in glutaminase activity may be one mechanism by which gut glutamine metabolism is diminished as the tumor grows and becomes the principal organ of glutamine use [26].
• Stereological estimates of the basal forebrain cell population in the rat, including neurons containing choline acetyltransferase, glutamic acid decarboxylase or phosphate-activated glutaminase and colocalizing vesicular glutamate transporters [27].

Analytical, diagnostic and therapeutic context of GLS

• By using chromosomal in situ hybridization, we have regionally mapped GLS to 2q32----q34 and IL9 to 5q31----q35 [15].
• In a novel finding using glutaminase-specific antibodies in combination with flow cytometry and confocal microscopy, glutaminase was shown to be present on the surface of human PMN [20].
• 78 patients with exfoliation syndrome were examined by one clinician (GLS), and underwent gonioscopy and dilated funduscopy [28].
• Patients undergoing arthroplasty demonstrated a decrease in serum GLS levels after the operations, but patients undergoing synovectomy did not, reflecting the extent of remaining or reproliferating synovial tissues rich in GLS production [29].
• Immunoassay systems were used to quantify GLS or cytokine levels in laboratory and clinical samples [30].

References