Disease relevance of GLUL

• Overexpression of glutamine synthetase in human primary liver cancer [1].
• RESULTS: Levels of GS were significantly increased in lumbar CSF from patients with AD (20+/-12 pg/mL; P = .01) and to a lesser extent in patients with vascular dementia and amyotrophic lateral sclerosis [2].
• METHODS: Sandwich enzyme immunoassay and immunoblotting were applied to detect GS in CSF and in serum from neurologically healthy control subjects and patients with neurodegenerative diseases, including AD [2].
• An inhibitor of exported Mycobacterium tuberculosis glutamine synthetase selectively blocks the growth of pathogenic mycobacteria in axenic culture and in human monocytes: extracellular proteins as potential novel drug targets [3].
• In RNA isolated from the endosymbiont there is a 10-fold reduction of GS transcript levels, a greater than 5-fold increase in 32-kd transcript levels and a greater than 5-fold decrease in RuBP carboxylase transcript levels, compared with levels in the free-living Anabaena azollae [4].

Psychiatry related information on GLUL

• Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder [5].
• The present results suggest the involvement of astrocytes in the regulation of the glutamatergic activation associated with withdrawal from free-choice ethanol consumption and point to differential adaptations of GS and GFAP to prolonged alcohol drinking in the PLC of P rats [6].
• It also leads us to suggest that some of the enzymes rapidly induced by glucocorticoids, such as glutamine synthetase, detoxify mediators released during stress-induced activation of primary defense mechanisms [7].
• Loss of glutamine synthetase activity in the brain in Huntington's disease [8].
• Oxidatively induced structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: relevance to Alzheimer's disease [9].

High impact information on GLUL

• Subsequently, we isolated a genomic clone for one locus on proximal chromosome 11 near the Glns locus, an imprinted region in uniparental disomic mice, and its corresponding cDNA clone [10].
• Glutamine synthetase: assimilatory role in liver as related to urea retention in marine chondrichthyes [11].
• The only nitrogen source utilizable by all studied isolates is ammonia, which is incorporated into glutamate by glutamine synthetase [12].
• Added to cultures of pathogenic mycobacteria, L-methionine- S-sulfoximine rapidly inhibited extracellular glutamine synthetase in a concentration-dependent manner but had only a minimal effect on cellular glutamine synthetase, a finding consistent with failure of the drug to cross the mycobacterial cell wall [3].
• The inhibitor L-methionine-S-sulfoximine rapidly inactivated purified M. tuberculosis glutamine synthetase, which was 100-fold more sensitive to this inhibitor than a representative mammalian glutamine synthetase [3].

Chemical compound and disease context of GLUL

• Glutamine, glutamine synthetase and Huntington's disease [13].
• These results show that GS is a potent neuroprotectant and that elevation of GS expression in glial cells activates an endogenous mechanism whereby neurons are protected from the deleterious effects of excess glutamate in extracellular fluid after trauma or ischemia [14].
• We also report that the free radical spin trap N-tert-butyl-alpha-phenylnitrone [300 mg/kg (body weight)] administered 60 min before ischemia/reperfusion is initiated, partially prevents protein oxidation and protects from loss of glutamine synthetase activity [15].
• Nitric oxide signaling gone awry: nitration of glutamine synthetase and hyperammonemia in sepsis [16].
• Regulation of glutamine synthetase by dexamethasone in hepatoma tissue culture cells [17].

Biological context of GLUL

• PCR analysis using three sets of primers designed from the reported sequences for GS cDNA and a processed pseudogene identified the corresponding BAC clones [18].
• The restriction analysis of the human insert DNAs provided a basis to divide these 18 BAC clones into five groups, suggesting the existence of a GS gene family in the human genome [18].
• Using human GS cDNA as a probe, a bacterial artificial chromosome (BAC) library consisting of two-fold coverage of the human genome was screened, and 18 clones were obtained [18].
• Localization of the L-glutamine synthetase gene to chromosome 1q23 [19].
• Upregulation of GS expression in hepatocellular carcinoma is related to growth advantage and an enhanced metastatic potential [20].

Anatomical context of GLUL

• CONCLUSIONS: Our results show an overexpression of GS in human primary liver cancers and, thus, point to its potential involvement in hepatocyte transformation [1].
• Immunoreactivity of GS was most prominent in astrocytes from temporal neocortex of patients with AD, suggesting a relationship between astrocyte reactions and increased GS levels in CSF [2].
• Glutamine synthetase in cerebrospinal fluid, serum, and brain: a diagnostic marker for Alzheimer disease [2]?
• Glutamine synthetase activity was equivalent in both non-epileptic and epileptic human neocortex [21].
• Expression of glutamine synthetase in macrophages [22].

Associations of GLUL with chemical compounds

• Glutamine synthetase (GS) is a ubiquitous enzyme that catalyzes the ATP-dependent conversion of glutamate to glutamine using ammonia as the nitrogen source [18].
• The quaternary structure of human brain GS at 10 microM (subunit concentration) was not significantly affected by cations, such as magnesium (5 and 20 mM) or manganese (0.2 and 1 mM) within the range of pH 7.1-7.8 [23].
• Creatine addition did not prevent this increment in S100B secretion, but was able to prevent the decrease in GFAP content and GS activity induced by ammonia exposure [24].
• Ethanol withdrawal significantly increased the packing density of GS- and GFAP-IR astrocytes in the PLC of P rats as compared with P rats with continuous access to ethanol [6].
• Both the astrocytes and the Müller glial cells reacted vigorously to kainate injection as shown by their up-regulated expression of nestin, glial fibrillary acidic protein and glutamine synthetase [25].

Regulatory relationships of GLUL

• This study examines the possible involvement of the glucocorticoid receptor (GR) in cell contact control of glutamine synthetase induction [26].
• Treatment of brain cell cultures with IL-1beta plus TNF-alpha was found to inhibit [3H]-glutamate uptake and astrocyte glutamine synthetase activity, two major pathways involved in NMDA receptor-related neurotoxicity [27].
• Participation of glutamine synthetase, glutamate synthase and NADP-dependent glutamate dehydrogenase was determined by inhibiting glutamine synthetase with phosphinothricin and glutamate synthase with azaserine [28].
• CONCLUSIONS: Glial glutamine synthetase is downregulated in the hippocampal sclerosis (HS) hippocampus of temporal lobe epilepsy (TLE) patients in areas with severe neuron loss [29].

Other interactions of GLUL

• Our findings shed some doubts on a role of glutamine synthetase in the pathophysiology of epilepsy in the neocortex [21].
• Therefore, oxidative inactivation of ENO1, GLUL and PIN1 may alter these cellular processes and lead to the development of AD from MCI [30].
• We found an increase in S100B secretion by astrocytes exposed to ammonia for 24h, accompanied by a decrease in GFAP content and GS activity [24].
• 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 [31].
• In two independent sets of two-dimensional gel electrophoresis/Western blots followed by peptide mass fingerprinting (PMF), nine proteins including voltage-dependent anion channel, enolase 1alpha, aldolase C, crystallins alphaA and betaB3, heterogeneous nuclear ribonucleoprotein A2/B1, albumin, and glutamine synthetase were identified [32].

Analytical, diagnostic and therapeutic context of GLUL

• A major GS transcript of 2.8 kilobase was detected by Northern blotting and sequencing [1].
• In addition, postmortem brain tissue from controls and patients with AD was analyzed using immunohistochemistry for expression of GS [2].
• Further localization of the glutamine synthetase gene locus to 1q23 was accomplished by fluorescence in situ hybridization [19].
• By use of confocal laser scanning microscopy and specific macrophage markers, immunoreactive glutamine synthetase was localized to macrophages in normal rat liver and normal human liver in situ [22].
• Sedimentation equilibrium profiles obtained from analytical ultracentrifugation experiments at 10 degrees C showed that human brain GS is mainly octameric [23].

References