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At least 19 recordsLinked to original sources
PubMed1977

Submitochondrial localization and function of enzymes of glutamine metabolism in avian liver.

Glutamine synthetase (EC 6.3.1.2) was localized within the matrix compartment of avian liver mitochondria. The submitochondrial localization of this enzyme was determined by the digitonin-Lubrol method of Schnaitman and Greenawalt (35). The matrix fraction contained over 74% of the glutamine synthetase activity and the major proportion of the matirx marker enzymes, malate dehydrogenase (71%), NADP-dependent isocitrate dehydrogenase (83%), and glutamate dehydrogenase (57%). The highest specific activities of these enzymes were also found in the matrix compartment. Oxidation of glutamine by avian liver mitochondria was substantially less than that of glutamate. Bromofuroate, an inhibitor of glutamate dehydrogenase, blocked oxidation of glutamate and of glutamine whereas aminoxyacetate, a transaminase inhibitor, had little or no effect with either substrate. These results indicate that glutamine metabolism is probably initiated by the conversion of glutamine to glutamate rather than to an alpha-keto acid. The localization of a glutaminase activity within avian liver mitochondria plus the absence of an active mitochondrial glutamine transaminase is consistent with the differential effects of the transaminase and glutamate dehydrogenase inhibitors. The high glutamine synthetase activity (40:1) suggests that mitochondrial catabolism of glutamine is minimal, freeing most of the glutamine synthesized for purine (uric acid) biosynthesis.

Animals↗
PubMed1975

Renal mitochondrial glutamine metabolism and dietary potassium and protein content.

Renal mitochondrial glutamine metabolism and dietary potassium and protein content. Glutamine distribution, glutamate accumulation, phosphate-dependent glutaminase (PDG) concentrations and intact mitochondrial ammonia production were studied in renal mitochondria from rats fed low, normal and high potassium diets and in mitochondria from rats fed high or low protein diets. The rats given a low potassium diet were potassium-depleted by 10 to 20% but in none of the groups were there any abnormalities of extracellular acid-base status. Glutamine was present in the outer space of mitochondria but could not be depleted in the matrix space in any group. In both the potassium-depleted and the high protein animals, we found increased matrix -14-C-uptake of glutamine (as -14-C-glutamate), increased intact mitochondrial ammonia production and increased concentrations of PDG. In the K+-depleted group there was a decreased matrix -14C-uptake when -14C-gamma-ketoglutarate of -14C-glutamate was present in the medium. Potassium loading produced no change in mitochondrial glutamine metabolism. Protein loading (compared with protein depletion) and potassium depletion induce an increased uptake of glutamine into the renal mitochondrial matrix space which leads to its increased deamidation. This adaption may explain the increased renal ammonia production seen in these situations when compared to their respective controls.

Ammonia↗
PubMed1976

[Regulation of fodder yeast Candida tropicalis glutamine synthetase activity by the end products of glutamine metabolism].

Effect of different products of glutamine metabolism on the activity of glutamine synthetase in the presence of Mg2+, and Mn2+ and Co2+ as cofactors is studied. All the metabolites studied are found to inhibit the glutamine synthetase activity in the presence of any cation listed. The degree and the character of the inhibition by one or other metabolite depended in a considerable degree on the nature of the cation presented in the reaction mixture (Mg2+, Mn2+ or Co2+). The mechanism of the cumulative effect of retroinhibitors under the change of Mg2+ or Mn2+ in the reaction mixture was the same.

Candida↗
PubMed1977

Acid-base induced alterations in glutamine metabolism and ureogenesis in perfused muscle and liver of the rat.

The effects of altered acid-base balance on the production of urea and the metabolism of glutamine were investigated in the isolated perfused liver and hindquarter of the rat. In the isolated perfused rat liver, lowering of perfusate pH without altering bicarbonate concentration significantly reduced urea production and increased net glutamine synthesis, although the converse did not obtain. In the isolated perfused rat hindquarter when perfusate pH and bicarbonate were simultaneously reduced glutamine synthesis was significantly increased. The combined hepatic and muscle increase in glutamine synthesis accounted for 89% of the decrease in hepatic urea synthesis under these experimental conditions. These changes in nitrogen metabolism are interpreted in terms of adaptations which offset the initial alterations in hydrogen ion homeostasis.

Acid-Base Imbalance↗
PubMed2026

PYCR1 promotes glutamine metabolism and the progression of lung adenocarcinoma by regulating the expression of OPLAH.

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Glutamine plays a critical role in the progression of LUAD. However, the function of pyrroline-5-carboxylate reductase 1 (PYCR1) and its regulatory role in glutamine metabolism remain unclear. Transcriptomic and clinical data for LUAD were obtained from The Cancer Genome Atlas (TCGA) and validated using Gene Expression Omnibus (GEO) datasets (GSE19188, GSE13213). Glutamine metabolism-related genes were analyzed for differential expression and prognostic significance. Functional enrichment was performed via gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses. Single-cell RNA-seq data (GSE117570) were processed using Seurat, and cell-cell communication was inferred with CellChat. In vitro, lentiviral overexpression, Western blotting, EdU, CCK-8, and glutamine uptake assays were conducted. An orthotopic xenograft model was established in nude mice to assess tumor growth in vivo. Six glutamine-metabolism-related genes were found significantly overexpressed in LUAD tissues and associated with poor overall survival. Single-cell sequencing revealed predominant PYCR1 expression in malignant cells. Functional assays demonstrated that PYCR1 overexpression enhanced glutamine uptake, proliferation, and inhibited apoptosis in LUAD cells, effects mediated via suppression of the P53 pathway. PYCR1 promoted tumor growth in a xenograft model and was found to transcriptionally upregulate 5-oxoprolinase (OPLAH), which augmented its oncogenic effects. Our findings identify the PYCR1/OPLAH axis as a key driver of LUAD progression via p53 signaling, revealing a promising therapeutic target.

Pyrroline Carboxylate Reductases↗
PubMed1977

[Regulation of glutamine metabolism in Chlorella pyrenoidosa. Regulation of glutamine synthetase activity by adenylic system components].

A decrease of glutamine synthetase (E. C. 6.3.1.2.) activity was observed under the assimilation of ammonium nitrogen in Chlorella. At the same time a decrease of ATP content in Chlorella cells took place. The ATP content was 7-fold decreased, while ADP and AMP contents were 4-fold and 3-fold increased respectively, after 15 min. of Chlorella incubation on "ammonium" medium. Further incubation for 45 min, resulted in gradual increase of ATP content and in decrease of ADP and AMP contents. The value of energy charge in ammonium assimilating Chlorella cells sharply decreased for first 15 min. of incubation and then it normalized gradually. The experiments with glutamine synthetase preparation, isolated from ammonium assimilating cells, have shown that ADP and AMP are strong inhibitors of the enzyme in the presence of Mg2+, and only ADP produces the inhibitory effect in the presence of Mn2+. No enzyme reactivation was observed after the transfer of ammonium assimilating cells into nitrogen-free medium or nitrate medium, the enzyme activity increasing at the expense of enzyme protein synthesis denovo.

Adenine Nucleotides↗
PubMedDate not supplied

[Specificity of glutamine metabolism in pre-tumorous diseases and cancer of the human stomach].

Content of free glutamine and the activity of glutamine synthetase and glutamine transaminase were studied in practically healthy persons and in patients with chronic atrophic gastritis, ulcerous disease, polyposis and with gastric carcinoma. The enzymatic activity was estimated in the areas of ulcerous impairment, of polypous vegetation of malignant neoplasm as well as in mucous membrane out of the impaired zone and in whole blood of all the patients studied. The tissues for biochemical tests were obtained by the directed gastrobiopsy. Content of glutamine was decreased in blood of patients with gastric carcinoma and increased in mucous membrane adjacent to the malignant tissue. Occurrence of the glutamine transaminase activity in the tissue areas studied was due to the specific glutamine metabolism during pretumoral diseases and gastric carcinoma, whereas the unimpaired gastric mucosa did not have the distinct enzymatic activity.

Alanine Transaminase↗
PubMed1975

Omega-aminoalkyl agaroses in the resolution of enzymes involved in regulation of glutamine metabolism.

Systematic examination of a homologous series of omega-aminoalkyl agaroses showed that the pentyl derivative (Seph-C5-NH2) was best suited for the retention and subsequent separation of several proteins involved in the regulation of glutamine metabolism in Escherichia coli, including: glutamine synthetase [EC 6.3.1.2; L-glutamate:ammonia ligase (ADP-forming)], ATP:glutamine synthetase adenylyltransferase (EC 2.7.7.42), the PII regulatory protein which regulates the adenylylation and deadenylylation activities of the adenylyltransferase, the UTP:PII protein uridylyltransferase, and the uridylyl removing enzyme which catalyzes the removal of uridylyl groups from uridylylated PII protein. Resolution of these proteins was achieved by gradually increasing the concentration of KCl in the eluant, which resulted in consecutive detachment of the proteins from the column. Proteins that co-elute from a DEAE-cellulose column can be resolved and further purified on epsilon-aminopentyl agarose, probably due to the fact that with the homologous series it is possible to adjust the contribution of hydrophobic interactions for optimal resolution.

ATP Phosphoribosyltransferase↗
PubMed1977

[Effect of arginine administration on disturbances of hepatic glutamine metabolism during acute ammonia intoxication in the rat].

The present study is concerned with the effects of L-arginine hydrochloride administration on the disturbances of liver glutamine metabolism following acute ammonia intoxication in the rat. Our results show that arginine administration does not suppress the decrease in the hepatic glutamine level and the marked activation of liver glutaminase I induced by ammonia. These alterations do not therefore appear to be related to the limitation of ammonia detoxication through the urea cycle.

Amino Acids↗
PubMed1976

[Glutamine metabolism regulation in Chlorella pyrenoidosa. Regulation of Chlorella glutamine synthetase activity by amino acids].

Effect of glutamine and its metabolites (amino acids) on Chlorella glutamine synthetase (GS) (E.C.6.3.1.2) in the presence of Mg or Mn was studied. Purified GS preparation was used, isolated from Chlorella grown in the presence of NH as a sole nitrogen source. Glutamate, aspartate, alanine and glycine inhibit GS activity in the presence of both Mg and Mn. Tryptophane and valine (up to 15 mM) activate GS in the presence of Mn. Tryptophane inhibits GS in the system with Mg. Sinergistic inhibition was observed under the combined effect of amino acids on GS in the presence of Mn and aspartate or alanine. The change of GS activity observed is supposed to be due to the inhibitory effect of glutamine and amino acids studied, since the glutamine content is increased (in 2.5 times for 5 min) and that of alanine and dicarbonic amino acids (for the following 15 min) under NH assimilation in Chlorella cells.

Amino Acids↗
PubMed1976

[Regulation of glutamine metabolism in Chlorella pyrenoidosa. Mechanisms of regulating the activity of glutamine synthetase during ammonia assimilation].

Glutamine synthetase (GS) (E.C.6.3.1.2) activity in Chlorella cells decreased when NH4+ was added to nitrogen-free growth medium. This GS inactivation had such a rate, that it could not be due to the repression of enzyme synthesis: the GS activity decreased by 20% within 5 minutes of NH4+ assimilation. Glutamine content in cell increased in 2.5 times for this period. In vitro experiments have shown that glutamine is a strong inhibitor of GS from Chlorella grown in the presence of NO3-, and in a less degree--an inhibitor of GS from cells grown in ammonium-containing medium. The data obtained are negative with respect to possible mechanisms of GS activity regulation via adenylation and ATP-dependent destruction of glutamine synthetase.

Ammonia↗
PubMed2026

Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.

BACKGROUND: Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined. METHODS: To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism. RESULTS: PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth. CONCLUSION: PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.

Journal Article↗
PubMed1979

Glutamine metabolism in nitrogen-starved conidia of Neurospora crassa.

During nitrogen deprivation, de novo synthesis of glutamine synthetase was induced in non-growing conidia of Neurospora crassa. When ammonia or glutamine was added to conidia which had been deprived of nitrogen, glutamine and arginine accumulated at a higher rate than in condia not deprived of nitrogen. The degradation of exogenous glutamine to glutamate is apparently a necessary step in the accumulation of glutamine and arginine within the conidia. In non-growing conidia, a cycle probably operates in which glutamine is degraded and resynthesized. The advantages of such a cycle would be that the carbon and nitrogen could be used to synthesize amino acids in general, as well as for the synthesis and accumulation of arginine and/or glutamine in particular.

Arginine↗
PubMed1976

Effect of para-aminohippurate on renal glutamine metabolism in the rat.

After para-aminohippurate (PAH) infusion into rats, urine pH decreased and urine ammonium excretion increased. Because augmented urine flow and decreased urine pH could not explain entirely the enhanced ammonium excretion, an increased ammonia production was postulated as a contributing influence. This was supported by the in vitro findings that PAH could increase slice ammoniagenesis from glutamine. The ability of PAH to stimulate ammoniagenesis in vitro was attributed to enhanced phosphate-dependent glutaminase activity. We conclude that PAH infusions at certain concentrations in vivo can alter ammonium excretion through increased renal ammonia production. The latter may be secondary to enhanced phosphate-dependent glutaminase activity.

Aerobiosis↗
PubMed2026

A novel glutamine metabolism-based classification system for characterizing the heterogeneity of hepatocellular carcinoma.

BACKGROUND: Glutamine dependence is a hallmark of tumor cell metabolism, and further molecular classification based on glutamine metabolism in patients with hepatocellular carcinoma (HCC) may provide clinical value. This study thus comprehensively examined the patterns of HCC-specific alterations in glutamine metabolism. METHODS: Consensus clustering analysis was conducted on samples from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset based on glutamine metabolism-related genes, which was validated in the GSE76427, the Liver Cancer-France (LICA-FR) cohort, and the Liver Cancer-Japan (LIRI-JP) cohort from the ICGC. Somatic mutation features were evaluated with the Maftools package in R. The activity of oncogenic pathways was estimated via gene set enrichment analysis (GSEA) or single-sample GSEA (ssGSEA). The tumor microenvironment was analyzed using both the CIBERSORT algorithm (for immune cell infiltration estimation) and the ESTIMATE algorithm (for stromal and immune score calculation). Drug sensitivity and immune checkpoint blockade (ICB) response were also analyzed, for which a classifier was built via least absolute shrinkage and selection operator (LASSO). Immunohistochemistry (IHC) was performed to validate the protein expression levels of key differentially expressed genes (DEGs). Intracellular glutamine content under different glutamine concentrations was measured. The viability of HCC cell lines under varying glutamine concentrations was assessed via Cell Counting Kit-8 (CCK-8) assays. Cell migration and invasion were evaluated through Transwell assays, and protein expression was analyzed via Western blotting. RESULTS: HCC samples were classified into two glutamine metabolism-based clusters, with cluster 1 having a more advanced stage of disease and shorter survival than cluster 2. A higher frequency of genetic mutations and stronger activation of oncogenic pathways was found in cluster 1. There were substantial differences in immune cell infiltration and stromal scores between clusters 1 and 2. Cluster 1 exhibited significantly higher infiltration of immunosuppressive cells and lower stromal scores compared to cluster 2. Cluster 1 had a stronger response to ICB due as indicated by a higher tumor mutation burden (TMB) and T cell-inflamed gene expression profile score, immune checkpoints, and Tumor Immune Dysfunction and Exclusion (TIDE)-predicted data. Moreover, the LASSO classifier accurately differentiated the two clusters. The DEGs between the two clusters were validated in clinical samples. IHC confirmed the differential expression of glutamine metabolism-related genes in HCC samples. CCK-8 assays showed no significant effect of glutamine concentration on cell proliferation. However, Transwell assays revealed that glutamine deprivation (0.2 mM) reduced migration and invasion, while high-glutamine conditions (10 mM) promoted them. Western blotting showed increased expression of metabolism-related proteins under high-glutamine conditions and reduced expression under deprivation. CONCLUSIONS: Altogether, these findings indicate the involvement of glutamine metabolism in HCC and may help inform patient stratification and the formulation of precision therapeutics for this population.

Hepatocellular carcinoma (HCC)↗
PubMed1978

gltB gene and regulation of nitrogen metabolism by glutamine synthetase in Escherichia coli.

A mutant (gltB) of Escherichia coli lacking glutamate synthase (GOGAT) was unable to utilize a wide variety of compounds as sole nitrogen source (e.g., arginine, proline, gamma-aminobutyrate, and glycine). Among revertants of these Asm- strains selected on one of these compounds (e.g., arginine, proline, or gamma-aminobutyrate) were those that produce glutamine synthetase (GS) constitutively (GlnC phenotype). These revertants had a pleiotropically restored ability to grow on compounds that are metabolized to glutamate. This suggested that the expression of the genes responsible for the metabolism of these nitrogen sources was regulated by GS. An examination of the regulation of proline oxidase confirmed this hypothesis. The differential sensitivities of GlnC and wild-type strains to low concentrations (0.1 mM) of the glutamine analog L-methionine-DL-sulfoximine supported the conclusion that the synthesis of a glutamine permease was also positively controlled by GS. During the course of this study we found that the reported position of the locus (gltB) for glutamate synthase is incorrect. We have relocated this gene to be 44% linked to the argG locus by P1 transduction. Further mapping has shown that the locus previously called aspB is in reality the gltB locus and that the "suppressor" of the aspB mutation (A. M. Reiner, J. Bacteriol. 97:1431-1436, 1969) is the locus for glutamate dehydrogenase (gdhA).

Ammonia↗
PubMed1976

Influence of aminooxyacetate administration on ammonia-induced metabolic disturbances in the rat liver.

The purpose of the present report was to investigate the effects of aminooxyacetate administration to rats on the ammonia-induced disturbances in the substrate levels and in the activities of the enzymes involved in glutamine metabolism. 1.--Aminooxyacetate enhances the accumulation of ammonia following an ammonia load and prevents the other substrate level changes induced by ammonia. Thus, this transaminase inhibitor suppresses ammonia detoxication by formation of aminoacids as well as by urea synthesis. 2.--A significant decrease of glutamine synthetase activity is observed only after administration of both aminooxyacetate and ammonium chloride. 3.--Like in rats injected with ammonium chloride alone, an ammonia-induced activation of liver glutaminase I is found in inhibitor-pretreated rats. This result confirms the specific enhancement of glutaminase I activity by ammonia in excess.

Acetates↗