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‣ Suplementação enteral e parenteral com glutamina em neonatos pré-termo e com baixo peso ao nascer; Enteral and parenteral supplementation with glutamine in preterm and low-birth-weight neonates

BORGES, Maria Carolina; ROGERO, Marcelo Macedo; TIRAPEGUI, Julio
Fonte: Divisão de Biblioteca e Documentação do Conjunto das Químicas da Universidade de São Paulo Publicador: Divisão de Biblioteca e Documentação do Conjunto das Químicas da Universidade de São Paulo
Tipo: Artigo de Revista Científica
Português
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A glutamina é o aminoácido livre mais abundante no sangue e no músculo esquelético, bem como é o principal substrato energético para células de elevado turnover, como enterócitos e leucócitos. Adicionalmente, a glutamina representa o principal aminoácido transferido para o feto pela placenta e, juntamente com o glutamato, constituem os aminoácidos mais abundantes no leite materno. Todavia, bebês nascidos prematuramente sofrem interrupção abrupta do fornecimento placentário de glutamina, o que acarreta em dependência exclusiva da síntese endógena ou do fornecimento exógeno deste aminoácido. Aliado a isso, neonatos pré-termo (PT) e com baixo peso ao nascer (BPN), freqüentemente, recebem apenas nutrição parenteral total nas primeiras semanas de vida, a qual não contém glutamina. Cabe ainda destacar que esses bebês possuem pouca massa muscular e, portanto, seus estoques de glutamina são limitados. Uma vez que neonatos PT e com BPN estão sujeitos a intenso crescimento e a inúmeros estresses fisiológicos, é possível que a glutamina seja um nutriente condicionalmente essencial nessa fase da vida, fato que estimulou a realização de estudos com a finalidade de avaliar os possíveis benefícios clínicos da suplementação enteral e parenteral com glutamina em neonatos PT e com BPN.; Glutamine is the most abundant amino acid found in the blood and skeletal muscle...

‣ Inhibition of assimilatory nitrate reductase activity in soil by glutamine and ammonium analogs.

McCarty, G W; Bremner, J M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/07/1992 Português
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Recent work in our laboratory indicated that the inhibitory effect of ammonium (NH4+) on assimilatory nitrate reductase (ANR) activity in soil is not due to NH4+ per se but to glutamine formed by microbial assimilation of NH4+. To test this conclusion, we studied the effects of eight analogs of L-glutamine (L-glutamic acid gamma-methyl ester, L-glutamic acid gamma-hydrazide, L-glutamic acid gamma-hydroxamate, L-glutamic acid gamma-ethyl ester, L-glutamic acid dimethyl ester, L-asparagine, L-aspartic acid beta-methyl ester, and L-aspartic acid beta-hydroxamate) and two analogs of ammonium (hydroxylamine and methylamine) on ANR activity in soil slurries. The studies with the L-glutamine analogs showed that all except L-glutamic acid dimethyl ester inhibited ANR activity in soil. The sharp contrast observed between the strong inhibitory effect of L-glutamic acid gamma-methyl ester on ANR activity and the complete lack of an inhibitory effect with the corresponding dimethyl ester suggests that only the free-acid form of glutamine effectively inhibits ANR activity. The studies with hydroxylamine and methylamine showed that both of these ammonium analogs inhibited ANR activity in soil and that this inhibition was dependent upon glutamine synthetase activity. This dependence indicates that inhibition of ANR activity by hydroxylamine and methylamine was due to formation of the glutamine analogs L-glutamic acid gamma-hydroxamate and L-glutamic acid gamma-methylamide...

‣ Observations on the pH Dependence of the Glutaminase Activity of a Glutamine Amidotransferase, Carbamylphosphate Synthetase

Trotta, Paul P.; Wellner, Vaira P.; Pinkus, Lawrence M.; Meister, Alton
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1973 Português
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Glutamine-dependent carbamylphosphate synthetase (Escherichia coli) is composed of a heavy subunit (molecular weight about 130,000) and a light subunit (molecular weight about 42,000), which can be separated with retention of catalytic activities. The separated heavy subunit can catalyze activation of CO2 by ATP and synthesis of carbamylphosphate from ammonia (but not from glutamine). The only catalytic activity exhibited by the separated light subunit is the ability to hydrolyze glutamine; the separated heavy subunit does not exhibit glutaminase activity. The pH-activity curve of the glutaminase activity of native carbamylphosphate synthetase exhibits maxima at about pH 4.2 and 9.5, while the glutaminase activity of the separated light subunit exhibits only a single optimum at about pH 6.7. When the light and heavy subunits are recombined, the two pH optima characteristic of native enzyme are restored. Glutaminase activities of native enzyme at both pH optima are similarly inhibited by the glutamine analog, L-2-amino-4-oxo-5-chloropentanoic acid, and also by dithiothreitol. Storage of native enzyme at pH 9 abolishes the glutaminase optimum at acid pH, but greatly increases the activity at alkaline pH. Treatment of native enzyme with N-ethylmaleimide increases the glutaminase activity dramatically and converts the pH profile to one that closely resembles that of the isolated light subunit. The data indicate that the same active site is involved in hydrolysis of glutamine at both acid and alkaline values of pH...

‣ Dependence of in vivo glutamine synthetase activity on ammonia concentration in rat brain studied by 1H - 15N heteronuclear multiple-quantum coherence-transfer NMR.

Kanamori, K; Ross, B D; Kuo, E L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/10/1995 Português
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The dependence of the in vivo rate of glutamine synthesis on the substrate ammonia concentration was studied in rat brain by 1H-15N heteronuclear multiple-quantum coherence-transfer NMR in combination with biochemical techniques. In vivo rates were measured at various steady-state blood and brain ammonia concentrations within the ranges 0.4-0.55 mumol/g and 0.86-0.98 mumol/g respectively, after low-rate intravenous 15NH4+ infusion (isotope chase). The rate of glutamine synthesis at steady state was determined from the change in brain [5-15N]glutamine levels during isotope chase, observed selectively through the amide proton by NMR, and 15N enrichments of brain glutamine and of blood and brain ammonia measured byN gas chromatography-MS. The in vivo rate (v) was 3.3-4.5 mumol/h per g of brain at blood ammonia concentrations (s) of 0.40-0.55 mumol/g. A linear increase of 1/v with 1/s permitted estimation of the in vivo glutamine synthetase (GS) activity at a physiological blood ammonia concentration to be 0.4-2.1 mumol/h per g. The observed ammonia-dependence strongly suggests that, under physiological conditions, in vivo GS activity is kinetically limited by sub-optimal in situ concentrations of ammonia as well as glutamate and ATP. Comparison of the observed in vivo GS activity with the reported in vivo rates of glutaminase and of gamma-aminobutyrate (GABA) synthesis suggests that...

‣ Glutamine transport by vesicles isolated from tumour-cell mitochondrial inner membrane.

Molina, M; Segura, J A; Aledo, J C; Medina, M A; Núnez de Castro, I; Márquez, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/06/1995 Português
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Mitochondrial-inner-membrane vesicles, isolated from Ehrlich ascites carcinoma cells by titration with detergents, accumulated L-glutamine by a very efficient transport system. The vesicles lack any phosphate-activated glutaminase activity, allowing measurement of transport rates without interference by L-glutamine metabolism. The time course of the transport was linear for the first 60 s, reaching a steady state after 120 min. L-Glutamine transport showed co-operativity, with a Hill coefficient of 2.2; the kinetic parameters S0.5 and Vmax had values of 5 mM and 26 nmol/30 s per mg of protein respectively. The pH-dependence curve showed a bell shape, with a pH optimum about 8.0. The uptake of L-glutamine was not affected by the presence of a 50-fold molar excess of D-glutamine, L-cysteine, L-histidine, L-alanine, L-serine and L-leucine, whereas L-glutamate behaved as a poor inhibitor. The structural analogue L-glutamate gamma-hydroxamate (5mM) inhibited the net uptake by 68%; interestingly, other analogues (6-diazo-5-oxo-L-norleucine, acivicin and L-glutamate gamma-hydrazide) were ineffective. The impermeant thiol reagent p-chloromercuriphenylsulphonic acid (0.5mM) completely abolished the mitochondrial L-glutamine uptake; in contrast...

‣ pH and temperature dependence of glutamine uptake, carbon dioxide and ammonia production in kidney slices from acidotic rats.

George, J P; Solomon, S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1981 Português
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1. The effects of medium pH and temperature on glutamine uptake, NH3 production and CO2 production were examined using kidney cortex slices from normal and acidotic rats. 2. Uptake of glutamine by kidney slices from normal rats shows a pH optimum of 7.5 at 25 degrees C and 7.3 at 37 degrees C. Uptake is optimal, however, at a constant OH-/H+ ratio of 10. 3. In slices from acidotic rats greatest uptake was at pH 6.8 at 25 degrees C and 6.6 at 37 degrees C. Optimal OH-/H+ ratio was 0.4 and constant at both temperatures. 4. CO2 production from glutamine was greatest at pH 7.0 at 37 degrees C in slices from control rats. No pH optimum was detected at 25 degrees C. With slices from acidotic animals, optimal pH for CO2 production became identical with that for uptake. 5. Both basal and glutamine-stimulated NH3 production showed no optimal pH but were significantly higher in slices from acidotic rats compared with those from controls. 6. Dependence of glutamine penetration on optimal OH-/H+ ratio is considered to reflect a general membrane phenomenon which is produced by either an increase in carrier-substrate complexes or an increase in the number of carriers at this ratio. 7. Cellular penetration of glutamine does not appear to be a limiting factor in production of NH3 in vitro.

‣ Analysis of kinetic, stoichiometry and regulation of glucose and glutamine metabolism in hybridoma batch cultures using logistic equations

Acosta, María Lourdes; Sánchez, Asterio; García, Francisco; Contreras, Antonio; Molina, Emilio
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
Português
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Batch cultures were carried out to study the kinetic, stoichiometry, and regulation of glucose and glutamine metabolism of a murine hybridoma line. Asymmetric logistic equations (ALEs) were used to fit total and viable cell density, and nutrient and metabolite/product concentrations. Since these equations were analytically differentiable, specific rates and yield coefficients were readily calculated. Asymmetric logistic equations described satisfactorily uncontrolled batch cultures, including death phase. Specific growth rate showed a Monod-type dependence on initial glucose and glutamine concentrations. Yield coefficients of cell and lactate from glucose, and cell and ammonium from glutamine were all found to change dramatically at low residual glucose and glutamine concentrations. Under stoichiometric glucose limitation, the glucose-to-cell yield increased and glucose-to-lactate yield decreased, indicating a metabolic shift. Under stoichiometric glutamine limitation the glutamine-to-cell and glutamine-to-ammonium yields increased, but also glucose-to-cell yield increased and the glucose-to-lactate yield decreased. Monoclonal antibody production was mainly non-growth associated, independently of glucose and glutamine levels.

‣ Pyruvate carboxylase is required for glutamine-independent growth of tumor cells

Cheng, Tzuling; Sudderth, Jessica; Yang, Chendong; Mullen, Andrew R.; Jin, Eunsook S.; Matés, José M.; DeBerardinis, Ralph J.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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Tumor cells require a constant supply of macromolecular precursors, and interrupting this supply has been proposed as a therapeutic strategy in cancer. Precursors for lipids, nucleic acids, and proteins are generated in the tricarboxylic acid (TCA) cycle and removed from the mitochondria to participate in biosynthetic reactions. Refilling the pool of precursor molecules (anaplerosis) is therefore crucial to maintain cell growth. Many tumor cells use glutamine to feed anaplerosis. Here we studied how “glutamine-addicted” cells react to interruptions of glutamine metabolism. Silencing of glutaminase (GLS), which catalyzes the first step in glutamine-dependent anaplerosis, suppressed but did not eliminate the growth of glioblastoma cells in culture and in vivo. Profiling metabolic fluxes in GLS-suppressed cells revealed induction of a compensatory anaplerotic mechanism catalyzed by pyruvate carboxylase (PC), allowing the cells to use glucose-derived pyruvate rather than glutamine for anaplerosis. Although PC was dispensable when glutamine was available, forcing cells to adapt to low-glutamine conditions rendered them absolutely dependent on PC for growth. Furthermore, in other cell lines, measuring PC activity in nutrient-replete conditions predicted dependence on specific anaplerotic enzymes. Cells with high PC activity were resistant to GLS silencing and did not require glutamine for survival or growth...

‣ Glutamine Synthetase Is a Genetic Determinant of Cell Type–Specific Glutamine Independence in Breast Epithelia

Kung, Hsiu-Ni; Marks, Jeffrey R.; Chi, Jen-Tsan
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Although significant variations in the metabolic profiles exist among different cells, little is understood in terms of genetic regulations of such cell type–specific metabolic phenotypes and nutrient requirements. While many cancer cells depend on exogenous glutamine for survival to justify the therapeutic targeting of glutamine metabolism, the mechanisms of glutamine dependence and likely response and resistance of such glutamine-targeting strategies among cancers are largely unknown. In this study, we have found a systematic variation in the glutamine dependence among breast tumor subtypes associated with mammary differentiation: basal- but not luminal-type breast cells are more glutamine-dependent and may be susceptible to glutamine-targeting therapeutics. Glutamine independence of luminal-type cells is associated mechanistically with lineage-specific expression of glutamine synthetase (GS). Luminal cells can also rescue basal cells in co-culture without glutamine, indicating a potential for glutamine symbiosis within breast ducts. The luminal-specific expression of GS is directly induced by GATA3 and represses glutaminase expression. Such distinct glutamine dependency and metabolic symbiosis is coupled with the acquisition of the GS and glutamine independence during the mammary differentiation program. Understanding the genetic circuitry governing distinct metabolic patterns is relevant to many symbiotic relationships among different cells and organisms. In addition...

‣ A metabolic perturbation by U0126 identifies a role for glutamine in resveratrol-induced cell death

Freeman, Michael R.; Kim, Jayoung; Lisanti, Michael P.; Di Vizio, Dolores
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em 01/12/2011 Português
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Recent evidence has identified substantial overlap between metabolic and oncogenic biochemical pathways, suggesting novel approaches to cancer intervention. For example, cholesterol lowering statins and the antidiabetes medication metformin both act as chemopreventive agents in prostate and other cancers. The natural compound resveratrol has similar properties: increasing insulin sensitivity, suppressing adipogenesis, and inducing apoptotic death of cancer cells in vitro. However, in vivo tumor xenografts acquire resistance to resveratrol by an unknown mechanism, while mouse models of metabolic disorders respond more consistently to the compound. Here we demonstrate that castration-resistant human prostate cancer C4-2 cells are more sensitive to resveratrol-induced apoptosis than isogenic androgen-dependent LNCaP cells. The MEK inhibitor U0126 antagonized resveratrol-induced apoptosis in C4-2 cells, but this effect was not seen with other MEK inhibitors. U0126 was found to inhibit mitochondrial function and shift cells to aerobic glycolysis independently of MEK. Mitochondrial activity of U0126 arose through decomposition, producing both mitochondrial fluorescence and cyanide, a known inhibitor of complex IV. Applying U0126 mitochondrial inhibition to C4-2 cell apoptosis...

‣ Glutamine versus Ammonia Utilization in the NAD Synthetase Family

De Ingeniis, Jessica; Kazanov, Marat D.; Shatalin, Konstantin; Gelfand, Mikhail S.; Osterman, Andrei L.; Sorci, Leonardo
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 15/06/2012 Português
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NAD is a ubiquitous and essential metabolic redox cofactor which also functions as a substrate in certain regulatory pathways. The last step of NAD synthesis is the ATP-dependent amidation of deamido-NAD by NAD synthetase (NADS). Members of the NADS family are present in nearly all species across the three kingdoms of Life. In eukaryotic NADS, the core synthetase domain is fused with a nitrilase-like glutaminase domain supplying ammonia for the reaction. This two-domain NADS arrangement enabling the utilization of glutamine as nitrogen donor is also present in various bacterial lineages. However, many other bacterial members of NADS family do not contain a glutaminase domain, and they can utilize only ammonia (but not glutamine) in vitro. A single-domain NADS is also characteristic for nearly all Archaea, and its dependence on ammonia was demonstrated here for the representative enzyme from Methanocaldococcus jannaschi. However, a question about the actual in vivo nitrogen donor for single-domain members of the NADS family remained open: Is it glutamine hydrolyzed by a committed (but yet unknown) glutaminase subunit, as in most ATP-dependent amidotransferases, or free ammonia as in glutamine synthetase? Here we addressed this dilemma by combining evolutionary analysis of the NADS family with experimental characterization of two representative bacterial systems: a two-subunit NADS from Thermus thermophilus and a single-domain NADS from Salmonella typhimurium providing evidence that ammonia (and not glutamine) is the physiological substrate of a typical single-domain NADS. The latter represents the most likely ancestral form of NADS. The ability to utilize glutamine appears to have evolved via recruitment of a glutaminase subunit followed by domain fusion in an early branch of Bacteria. Further evolution of the NADS family included lineage-specific loss of one of the two alternative forms and horizontal gene transfer events. Lastly...

‣ Temperature dependence of molecular interactions involved in defining stability of Glutamine Binding Protein and its complex with L-Glutamine†

Pistolesi, Sara; Tjandra, Nico
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Temperature dependence of dynamic parameters derived from nuclear magnetic resonance (NMR) relaxation data are related to conformational entropy of the system under study. This provides information such as macromolecules stability and thermodynamics of ligand binding. We studied the temperature dependence of NMR order parameter of Glutamine binding protein (GlnBP), a periplasmic binding protein (PBP) highly specific to L-glutamine associated with its ABC transporter, with the goal of elucidating the dynamical differences between the respective ligand bound and free forms. We found that the protein-ligand interaction, which is stabilized at higher temperature, has a striking effect on the stability of the hydrophobic core of the large domain of GlnBP. Moreover, in contrast to what was found for less specific PBPs the decreasing backbone motion of the hinge region at increasing temperature supports the idea that the likelihood that GlnBP can adopt a ligand free closed conformation in solution diminishes at higher temperatures. Our results support the induced-fit model as mode of action for GlnBP. In addition, we found that the backbones of residues involved in a salt bridge do not necessarily become more rigid as the temperature rises as it was previously suggested [Vinther...

‣ Glutamine and cancer: cell biology, physiology, and clinical opportunities

Hensley, Christopher T.; Wasti, Ajla T.; DeBerardinis, Ralph J.
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Português
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Glutamine is an abundant and versatile nutrient that participates in energy formation, redox homeostasis, macromolecular synthesis, and signaling in cancer cells. These characteristics make glutamine metabolism an appealing target for new clinical strategies to detect, monitor, and treat cancer. Here we review the metabolic functions of glutamine as a super nutrient and the surprising roles of glutamine in supporting the biological hallmarks of malignancy. We also review recent efforts in imaging and therapeutics to exploit tumor cell glutamine dependence, discuss some of the challenges in this arena, and suggest a disease-focused paradigm to deploy these emerging approaches.

‣ Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer

Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S.; Marini, Juan; Zhao, Hongyun; Wahlig, Stephen; Armaiz-Pena, Guillermo; Jiang, Dahai; Achreja, Abhinav; Win, Julia; Roopaimoole, Rajesha; Rodriguez-Aguayo, Cristian; Mercado-Uribe, Imelda; Lopez-Berestein,
Fonte: Universidade Rice Publicador: Universidade Rice
Tipo: Journal article; Text; publisher version
Português
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Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.

‣ Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer

Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S; Marini, Juan; Zhao, Hongyun; Wahlig, Stephen; Armaiz‐Pena, Guillermo; Jiang, Dahai; Achreja, Abhinav; Win, Julia; Roopaimoole, Rajesha; Rodriguez‐Aguayo, Cristian; Mercado‐Uribe, Imelda; Lopez‐Bere
Fonte: European Molecular Biology Organization Publicador: European Molecular Biology Organization
Tipo: Artigo de Revista Científica
Publicado em 05/05/2014 Português
Relevância na Pesquisa
37.66376%
Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.

‣ Glutamate and asparagine cataplerosis underlie glutamine addiction in melanoma

Ratnikov, Boris; Aza-Blanc, Pedro; Ronai, Ze'ev A.; Smith, Jeffrey W.; Osterman, Andrei L.; Scott, David A.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 28/02/2015 Português
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Glutamine dependence is a prominent feature of cancer metabolism, and here we show that melanoma cells, irrespective of their oncogenic background, depend on glutamine for growth. A quantitative audit of how carbon from glutamine is used showed that TCA-cycle-derived glutamate is, in most melanoma cells, the major glutamine-derived cataplerotic output and product of glutaminolysis. In the absence of glutamine, TCA cycle metabolites were liable to depletion through aminotransferase-mediated α-ketoglutarate-to-glutamate conversion and glutamate secretion. Aspartate was an essential cataplerotic output, as melanoma cells demonstrated a limited capacity to salvage external aspartate. Also, the absence of asparagine increased the glutamine requirement, pointing to vulnerability in the aspartate-asparagine biosynthetic pathway within melanoma metabolism. In contrast to melanoma cells, melanocytes could grow in the absence of glutamine. Melanocytes use more glutamine for protein synthesis rather than secreting it as glutamate and are less prone to loss of glutamate and TCA cycle metabolites when starved of glutamine.

‣ Targeting SLC1A5-mediated glutamine dependence in non-small cell lung cancer

Hassanein, Mohamed; Qian, Jun; Hoeksema, Megan D.; Wang, Jing; Jacobovitz, Marie; Ji, Xiangming; Harris, Fredrick T.; Harris, Bradford K.; Boyd, Kelli L.; Chen, Heidi; Eisenberg, Rosana; Massion, Pierre P.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-L-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p =0.01, HR =1.24, 95% CI: 1.05–1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001...

‣ Glutamine Substitution at Alanine1649 in the S4–S5 Cytoplasmic Loop of Domain 4 Removes the Voltage Sensitivity of Fast Inactivation in the Human Heart Sodium Channel

Tang, Lihui; Chehab, Nabil; Wieland, Steven J.; Kallen, Roland G.
Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/05/1998 Português
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Normal activation–inactivation coupling in sodium channels insures that inactivation is slow at small but rapid at large depolarizations. M1651Q/M1652Q substitutions in the cytoplasmic loop connecting the fourth and fifth transmembrane segments of Domain 4 (S4–S5/D4) of the human heart sodium channel subtype 1 (hH1) affect the kinetics and voltage dependence of inactivation (Tang, L., R.G. Kallen, and R. Horn. 1996. J. Gen. Physiol. 108:89–104.). We now show that glutamine substitutions NH2-terminal to the methionines (L1646, L1647, F1648, A1649, L1650) also influence the kinetics and voltage dependence of inactivation compared with the wild-type channel. In contrast, mutations at the COOH-terminal end of the S4–S5/D4 segment (L1654, P1655, A1656) are without significant effect. Strikingly, the A1649Q mutation renders the current decay time constants virtually voltage independent and decreases the voltage dependences of steady state inactivation and the time constants for the recovery from inactivation. Single-channel measurements show that at negative voltages latency times to first opening are shorter and less voltage dependent in A1649Q than in wild-type channels; peak open probabilities are significantly smaller and the mean open times are shorter. This indicates that the rate constants for inactivation and...

‣ Characteristics of L-glutamine transport in perfused rat skeletal muscle.

Hundal, H S; Rennie, M J; Watt, P W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1987 Português
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1. We have investigated glutamine transport in the perfused rat hindlimb using the paired-tracer isotope dilution technique. 2. Uptake of L-glutamine was stereospecific, saturable, sodium dependent, insulin sensitive and pH insensitive in the physiological range. The maximum capacity of transport (Vmax) under normal perfusate conditions at 37 degrees C, 145 mM-Na+ and in the absence of insulin was 1156 +/- 193 nmol min-1 g-1 with transport being half-maximal at a perfusate glutamine concentration of 9.25 +/- 1.15 mM. 3. The kinetics of Na+ dependence strongly suggested co-transport of Na+ and glutamine with a stoichiometry of 1:1; furthermore, Na+ activated the carrier without any change in the concentration of glutamine at which transport was half-maximal, i.e. a 'Vmax effect' rather than a 'Km effect'. 4. The characteristics of glutamine transport, especially its substrate specificity and the pattern of competitive and non-competitive inhibition of glutamine transport by other amino acids, suggest that it is mediated by a carrier or carriers for which asparagine and histidine are also suitable substrates. 5. The characteristics of muscle glutamine transport are related but distinct from those of system N identified in hepatocytes; we suggest that they are sufficiently distinct to justify the identification of a new variant of mammalian amino acid transport systems which may be identified by the symbol Nm. 6. The kinetic characteristics of system Nm are such that glutamine is likely to be the most rapidly exchanging amino acid across the muscle membrane at physiological intra- and extracellular glutamine concentrations. Its hormone and ion sensitivities are likely to be important in the physiological modulation of whole-body glutamine metabolism and also during derangements observed in disease and after injury.

‣ Enteral and parenteral supplementation with glutamine in preterm and low-birth-weight neonates; Suplementação enteral e parenteral com glutamina em neonatos pré-termo e com baixo peso ao nascer

Borges, Maria Carolina; Rogero, Marcelo Macedo; Tirapegui, Julio
Fonte: Universidade de São Paulo. Faculdade de Ciências Farmacêuticas Publicador: Universidade de São Paulo. Faculdade de Ciências Farmacêuticas
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; Artigo Avaliado pelos Pares Formato: application/pdf
Publicado em 01/03/2008 Português
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Glutamine is the most abundant amino acid found in the blood and skeletal muscle, and is the principal energetic substrate for cells with a high turnover, such as enterocytes and leucocytes. Furthermore, glutamine is the most important amino acid that is passed to the foetus via the placenta, and together with glutamate, is the most abundant amino acid in maternal milk. Preterm infants suffer an abrupt interruption in the supply of glutamine via the placenta, which leads to an exclusive dependence on the endogenous synthesis or the exogenous supply of this amino acid. Preterm neonates (PT) as well as low-birth-weight neonates (LBW) frequently receive only total parenteral nutrition during their first weeks of life, which contains no glutamine. It must be pointed out that these infants present low muscular mass and that therefore, their stock of glutamine is limited. Because PT and BPN neonates are subject to intensive growth periods and numerous physiological stresses, it is possible that glutamine is a conditionally essential nutrient in this stage of life, thus giving foundation for the pursuit of studies aiming at the evaluation of the possible clinical benefits of enteral and parenteral supplementation with glutamine in PT and BPN neonates.; A glutamina é o aminoácido livre mais abundante no sangue e no músculo esquelético...