Disease relevance of Gls

• Our results suggest that inhibition of glutaminase expression using anti-sense technology induces phenotypic changes in Ehrlich ascites tumor cells that allow the development of an effective anti-tumor immune response, which makes the cells unable to develop in vivo tumors [1].
• Mice bearing the Lewis lung carcinoma showed a high tumour glutaminase activity and significantly higher concentrations of most amino acids than in both the liver and the skeletal muscle of the host [2].
• AVET-transfected keratinocytes derived from keratinocyte trans- glutaminase negative lamellar ichthyosis patients with a CMV-TGK expression plasmid showed that it is possible to reach a level of total enzyme activity similar to that found in cultured keratinocytes from normal individuals [3].
• Changes in phosphate-activated glutaminase activities determined in intact cells and isolated mitochondria have been followed during mouse Ehrlich ascites carcinoma development [4].
• Pseudomonas 7A glutaminase reduced the survival of cells in glutamine-free culture and prevented growth of spheroids [5].

High impact information on Gls

• The levels of free glutamine in plasma and tissues, and the activities of glutamine synthetase and glutaminase, tended to approach normal values in the last days of life of the tumor-transplanted animals [6].
• Unlike results reported with glutaminase and asparaginase preparations, the lactate dehydrogenase-elevating virus had no significant influence on plasma clearance of tyrosine phenol-lyase [7].
• Here we have shown that TNF-alpha is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity [8].
• In vivo, mtGSH depletion in B16M-F10 cells was achieved by feeding mice (where the B16M-F10 grew as a solid tumor in the footpad) with an L-glutamine (L-Gln)-enriched diet, which promoted in the tumor cells an increase in glutaminase activity, accumulation of cytosolic L-glutamate, and competitive inhibition of GSH transport into mitochondria [9].
• We rescued neuronal cell death in vitro by using a glutaminase inhibitor or hemichannel blockers to diminish microglial glutamate release without perturbing the physiological glutamate level [8].

Chemical compound and disease context of Gls

• Glutamatergic or GABAergic neuron-specific, long-term expression in neocortical neurons from helper virus-free HSV-1 vectors containing the phosphate-activated glutaminase, vesicular glutamate transporter-1, or glutamic acid decarboxylase promoter [10].
• The short-term metabolic fate of labeled nitrogen derived from [13N]ammonia or from L-[amide-13N]glutamine was determined in murine tumors known to be resistant (Ridgeway Osteogenic Sarcoma (ROS] or sensitive (Sarcoma-180 (S-180)) to glutaminase therapy [11].
• In the present study, glutaminase purified from human ovarian cancer ascites fluid was used in experimental solid and ascites mice model alone and in combination with Cu-Sulphate and heparin [12].

Biological context of Gls

• The human gene maps to chromosome 2q34-q36, and the mouse gene is localized to the syntenic region of chromosome 1 (between markers Gls and Acrg) [13].
• A glutaminase (gis) gene maps to mouse chromosome 1, rat chromosome 9, and human chromosome 2 [14].
• Relative stage-specific expression of glutaminase RNA was assessed by reverse transcription polymerase chain reaction (RT-PCR) in embryos that developed both in vivo and in CZB culture [15].
• The cumulative data indicate the following: 1) excitotoxic neuronal death activates the hydrolysis of extracellular glutamine by the mitochondrial glutaminase, and 2) the glutaminase in damaged neurons is sufficient to cause neuronal death in in vitro models of neuronal injury [16].
• The present results suggest that (i) short-term changes of glutamine concentration have small effects on cell viability; and (ii) depletion of glutamine levels in blood through the in vivo use of glutaminase is unlikely to produce major therapeutic effects against nutrient-deprived cells in solid tumours [5].

Anatomical context of Gls

• Similarly, human-hamster somatic cell hybrids were examined for RFLPs, and four human EcoRI restriction fragments were found to hybridize with the rat glutaminase probe [14].
• In vivo, glutaminase RNA was expressed at the 1-cell stage, declined to 23% of 1-cell levels at the early 2-cell stage, and reaccumulated from late 2-cell through blastocyst stage, where it reached a high of 204% of 1-cell levels [15].
• Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels [17].
• Phosphate activated glutaminase activity and glutamine uptake in primary cultures of astrocytes [18].
• Using anti-sense technology, an Ehrlich ascites tumor cell line (0.28AS-2) with reduced glutaminase activity has been obtained [1].

Associations of Gls with chemical compounds

• Glutaminase is the enzyme responsible for the conversion of glutamine to glutamic acid, which then enters the trichloro acetic acid (TCA) cycle as alpha-ketoglutarate [15].
• Increased production of extracellular glutamate by the mitochondrial glutaminase following neuronal death [16].
• These patterns are indicative of a hybrid ping-pong mechanism consisting of a glutaminase partial reaction and a sequential catalysis involving aspartate and ATP [19].
• Inhibition patterns of the four products, glutamate, AMP, PPi, and asparagine, versus each of the three substrates are consistent with a hybrid Uni Uni Bi Ter Ping Pong Theorell-Chance mechanism where the glutaminase reaction occurs first and aspartate binds to the enzyme before ATP in the sequential segment [19].
• Glutamate generation by damaged neurons was dependent on the presence of glutamine, activated by phosphate, and inhibited by 6-diazo-5-oxo-L-norleucine and p-chloromercuriphenylsulfonic acid (pCMPS), strongly implicating the mitochondrial glutaminase [16].

Physical interactions of Gls

• Kinetics of uptake and activity in mouse liver of glutaminase coupled to desialated orosomucoid [20].

Other interactions of Gls

• Analysis of chromosome 1 alleles for several genes in an interspecific cross between Mus spretus and C3H/HeJ-gld/gld mice indicates that glutaminase can be positioned within 5.5 +/- 2.0 cM proximal to Ctla-4 [14].
• The homologues of the Cryg, Gls, and Aox genes have been mapped on mouse chromosome 1 and human chromosome 2q [21].
• In agreement with this observation, activities of the ammoniagenic enzymes, glutaminase and glutamate dehydrogenase, were not different in the renal cortex of fed and starved mice, but the glutamate dehydrogenase mRNA level was elevated 4.5-fold in the renal cortex from starved mice [22].
• Further evidence for the role of glutamine conversion to glutamate was obtained with the glutaminase inhibitor 6-diazo-5-oxo-l-norleucine (DON), which inhibited the effect of glutamine on heat-induced Hsp25 [23].
• Of the genes that detoxify ammonia generated from protein catabolism, hepatic glutaminase, carbamyl phosphate synthase I, and tyrosine aminotransferase mRNAs increased 2.4-, 1.8-, and 1.8-fold with CR, respectively [24].

Analytical, diagnostic and therapeutic context of Gls

• Glutaminase had no effect on cell survival in the Lewis lung tumour or in MGH-U1 xenografts, with or without radiation; glutaminase caused dose-dependent growth delay of the KHT tumour, which was additive to that caused by radiation [5].
• Bacterial glutaminase was shown to be effective in lowering the tumor burden with increased life span of the host [25].
• Northern blot analysis indicated that two species of glutaminase mRNA were expressed in the spleen, which showed a differential expression pattern during the first 2 days after tumor implantation [26].
• Phosphate dependent glutaminase enzyme purified from mitochondria of malignant and non malignant ovarian tissue also showed bands of same molecular weight on 10% SDS-PAGE and gave same immunoreactive bands in trans-immunoblot like the purified glutaminase from ascites fluid [27].
• In several investigations, bacterial glutaminase was found to be a potent therapeutic agent against varieties of tumor, but it showed suppressive effects on haematopoietic systems and inhibitory effects on normal lymphocytic blastogenesis [28].

References