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mTOR inhibitor-mediated suppression of glycolysis results in a compensatory increase in glutaminolysis.
May 18, 2018: Cancer Discovery
Shun-Ichi Matsuura, Manami Chiba, Tatsuo Tsunoda, Aritomo Yamaguchi
Direct enzyme immobilization by encapsulation in the pores of mesoporous silica particles enhances protein thermal and chemical stability. In this study, we investigated the effect of pore size on the thermostability and catalytic activity of Escherichia coli glutaminase YbaS encapsulated under high temperature conditions in two SBA-type mesoporous silicas: SBA5.4 and SBA10.6 with pore diameters of 5.4 and 10.6 nm, respectively. The changes in enzyme conformation under high temperature conditions were assessed using PSA, a benzophenoxazine-based fluorescent dye that is sensitive to denatured aggregated proteins...
January 1, 2018: Journal of Nanoscience and Nanotechnology
Milica Momcilovic, Sean T Bailey, Jason T Lee, Michael C Fishbein, Daniel Braas, James Go, Thomas G Graeber, Francesco Parlati, Susan Demo, Rui Li, Tonya C Walser, Michael Gricowski, Robert Shuman, Julio Ibarra, Deborah Fridman, Michael E Phelps, Karam Badran, Maie St John, Nicholas M Bernthal, Noah Federman, Jane Yanagawa, Steven M Dubinett, Saman Sadeghi, Heather R Christofk, David B Shackelford
Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3α/β signaling pathway, which upregulates glutaminolysis. Phospho-GSK3α/β protein levels are predictive of response to single-therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance...
May 14, 2018: Cancer Cell
Michael J Lukey, William P Katt, Richard A Cerione
Identifying contexts in which cancer cells become addicted to specific nutrients is critical for developing targeted metabolic therapies. In this issue of Cancer Cell, Momcilovic et al. report that suppressed glycolysis following mTOR inhibition is countered by adaptive glutamine catabolism in lung squamous cell carcinoma, sensitizing tumors to glutaminase inhibition.
May 14, 2018: Cancer Cell
Jiaqiu Li, Ping Song, Tingting Jiang, Dongjun Dai, Hanying Wang, Jie Sun, Liyuan Zhu, Wenxia Xu, Lifeng Feng, Vivian Y Shin, Helen Morrison, Xian Wang, Hongchuan Jin
Heat shock factor 1 (HSF1) generally exhibits its properties under stress conditions. In tumors, HSF1 has a pleiotropic feature in regulating growth, survival, and aggressiveness of cancer cells. In this study, we found HSF1 was increased in colorectal cancer (CRC) and had a positive correlation with shorter disease-free survival (DFS). Knockdown of HSF1 in CRC cells attenuated their growth while inhibiting mTOR activation and glutamine metabolism. HSF1 inhibited the expression of microRNA137 (MIR137), which targeted GLS1 (glutaminase 1), thus stimulating GLS1 protein expression to promote glutaminolysis and mTOR activation...
April 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Yiwei Sun, Xiaohe Feng, Xuanli Liu, Cheng Qian, Xin Che, Fei Cao, Sanshan Jin, Dali Meng
Human kidney-type glutaminase (KGA) is an important target that is often over expressed in many cancer cells but very few effective inhibitors of this enzyme have yet reached clinical trials. Caudatan A and caudatan B, two undescribed tetracyclic flavans with an unusual ether bond between the C-4 and C-2' were isolated from the roots of Ohwia caudata (Thunb.) H.Ohashi. Caudatan A exhibited stronger inhibitory activity and caudatan B showed moderate effect from the results of inhibitory activities evaluations on KGA...
April 28, 2018: Phytochemistry
Paula Moyano, María Teresa Frejo, María José Anadon, José Manuel García, María Jesús Díaz, Margarita Lobo, Emma Sola, Jimena García, Javier Del Pino
Chlorpyrifos (CPF) is an organophosphate insecticide described to induce cognitive disorders, both after acute and repeated administration. However, the mechanisms through which it induces these effects are unknown. CPF has been reported to produce basal forebrain cholinergic neuronal cell death, involved on learning and memory regulation, which could be the cause of such cognitive disorders. Neuronal cell death was partially mediated by oxidative stress generation, P75NTR and α7 -nAChRs gene expression alteration triggered through acetylcholinesterase (AChE) variants disruption, suggesting other mechanisms are involved...
April 14, 2018: Toxicology
Mariko Kato Hayashi
Many kinds of transporters contribute to glutamatergic excitatory synaptic transmission. Glutamate is loaded into synaptic vesicles by vesicular glutamate transporters to be released from presynaptic terminals. After synaptic vesicle release, glutamate is taken up by neurons or astrocytes to terminate the signal and to prepare for the next signal. Glutamate transporters on the plasma membrane are responsible for transporting glutamate from extracellular fluid to cytoplasm. Glutamate taken up by astrocyte is converted to glutamine by glutamine synthetase and transported back to neurons through glutamine transporters on the plasma membranes of the astrocytes and then on neurons...
April 12, 2018: International Journal of Molecular Sciences
Francisco Leisico, Diana V Vieira, Teresa A Figueiredo, Micael Silva, Eurico J Cabrita, Rita G Sobral, Ana Madalena Ludovice, José Trincão, Maria João Romão, Hermínia de Lencastre, Teresa Santos-Silva
Gram-positive bacteria homeostasis and antibiotic resistance mechanisms are dependent on the intricate architecture of the cell wall, where amidated peptidoglycan plays an important role. The amidation reaction is carried out by the bi-enzymatic complex MurT-GatD, for which biochemical and structural information is very scarce. In this work, we report the first crystal structure of the glutamine amidotransferase member of this complex, GatD from Staphylococcus aureus, at 1.85 Å resolution. A glutamine molecule is found close to the active site funnel, hydrogen-bonded to the conserved R128...
March 28, 2018: Scientific Reports
Liping Zhao, Juan Qiao, Ke Zhang, Dan Li, Hongyi Zhang, Li Qi
A chiral ligand exchange capillary electrochromatography (CLE-CEC) protocol was designed and implemented for d,l-amino acids enantioseparation with poly(maleic anhydride-styrene-methacryloyl-l-arginine methyl ester) as the coating. The block copolymer was synthesized through the reversible addition fragmentation chain transfer reaction. In the constructed CLE-CEC system, poly (methacryloyl-l-arginine methyl ester) moiety of the block copolymer played the role as the immobilized chiral ligand and Zn (II) was used as the central ion...
March 15, 2018: Journal of Chromatography. A
Russell A Miller, Yuji Shi, Wenyun Lu, David A Pirman, Aditi Jatkar, Matthew Blatnik, Hong Wu, César Cárdenas, Min Wan, J Kevin Foskett, Junyoung O Park, Yiyi Zhang, William L Holland, Joshua D Rabinowitz, Morris J Birnbaum
Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood...
March 26, 2018: Nature Medicine
Elisabeth F P Peterse, Bertine Niessen, Ruben D Addie, Yvonne de Jong, Arjen H G Cleven, Alwine B Kruisselbrink, Brendy E W M van den Akker, Remco J Molenaar, Anne-Marie Cleton-Jansen, Judith V M G Bovée
INTRODUCTION: Chondrosarcoma is a malignant cartilage-forming bone tumour in which mutations in IDH1 and IDH2 frequently occur. Previous studies suggest an increased dependency on glutaminolysis in IDH1/2 mutant cells, which resulted in clinical trials with the drugs CB-839, metformin and chloroquine. In this study, the preclinical rationale for using these drugs as a treatment for chondrosarcoma was evaluated. METHODS: Expression of glutaminase was determined in 120 cartilage tumours by immunohistochemistry...
March 26, 2018: British Journal of Cancer
Saiful Islam, Masashi Ueda, Emika Nishida, Miao-Xing Wang, Masatake Osawa, Dongsoo Lee, Masanori Itoh, Kiyomi Nakagawa, Tana, Toshiyuki Nakagawa
Olfaxin, which is a BNIP2 and Cdc42GAP homology (BCH) domain-containing protein, is predominantly expressed in mitral and tufted (M/T) cells in the olfactory bulb (OB). Olfaxin and Caytaxin, which share 56.3% amino acid identity, are similar in their glutamatergic terminal localization, kidney-type glutaminase (KGA) interaction, and caspase-3 substrate. Although the deletion of Caytaxin protein causes human Cayman ataxia and ataxia in the mutant mouse, the function of Olfaxin is largely unknown. In this study, we generated Prune2 gene mutant mice (Prune2Ex16-/- ; knock out [KO] mice) using the CRISPR/Cas9 system, during which the exon 16 containing start codon of Olfaxin mRNA was deleted...
March 20, 2018: Brain Research
Toby Wise, Matthew J Taylor, Andres Herane-Vives, Antonella Marino Gammazza, Francesco Cappello, David J Lythgoe, Steve Cr Williams, Allan H Young, Anthony J Cleare, Danilo Arnone
BACKGROUND: There is uncertainty as to whether alterations in glutamatergic function in affective disorders differ between unipolar and bipolar disorders and between depressive and euthymic states. Additionally, there are currently no available blood-based markers of central glutamatergic function to support clinical diagnosis and aid brain based investigations. METHODS: In this study, we measured levels of glutamate in the dorsal anterior cingulate cortex in-vivo using 1H-Magnetic Resonance Spectroscopy in medication free unipolar and bipolar patients (n = 29, 20 unipolar and 9 bipolar) experiencing a major depressive episode, in comparison with a group of matched healthy controls (n = 20)...
February 27, 2018: Journal of Affective Disorders
Antonio Gil-Gomez, Ana Isabel Gómez-Sotelo, Isidora Ranchal, Ángela Rojas, Marta García-Valdecasas, Rocío Muñoz-Hernández, Rocío Gallego-Durán, Javier Ampuero, Manuel Romero Gómez
AIM: to analyze the effect of metformin on ammonia production derived from glutamine metabolism in vitro and in vivo. METHODS: twenty male Wistar rats were studied for 28 days after a porto-caval anastomosis (n = 16) or a sham operation (n = 4). Porto-caval shunted animals were randomized into two groups (n = 8) and either received 30 mg/kg/day of metformin for two weeks or were control animals. Plasma ammonia concentration, Gls gene expression and K-type glutaminase activity were measured in the small intestine, muscle and kidney...
March 15, 2018: Revista Española de Enfermedades Digestivas
Balraj Singh, Vanessa N Sarli, Laura J Washburn, Milan R Raythatha, Anthony Lucci
We previously described a strategy for selecting highly adaptable rare triple-negative breast cancer (TNBC) cells based on their ability to survive a severe and prolonged metabolic challenge, e.g., a lack of glutamine. We hypothesized that metabolically adaptable (MA) cancer cells selected from the SUM149 cell line in this manner have the capacity to survive a variety of challenges that postulated "decathlon winner" cancer cells must survive to succeed in metastasis. These MA cells were resistant to glutaminase inhibitor CB-839, as predicted from their ability to proliferate without exogenous glutamine...
February 16, 2018: Oncotarget
Beiqing Wu, Jianhui Liu, Runze Zhao, Yuju Li, Justin Peer, Alexander L Braun, Lixia Zhao, Yi Wang, Zenghan Tong, Yunlong Huang, Jialin C Zheng
BACKGROUND: Extracellular vesicles (EVs) are important in the intercellular communication of the central nervous system, and their release is increased during neuroinflammation. Our previous data demonstrated an increased release of EVs during HIV-1 infection and immune activation in glial cells. However, the molecular mechanism by which infection and inflammation increase EV release remains unknown. In the current study, we investigated the role of glutaminase 1 (GLS1)-mediated glutaminolysis and the production of a key metabolic intermediate α-ketoglutarate on EV release...
March 14, 2018: Journal of Neuroinflammation
Tianyu Han, Weihua Zhan, Mingxi Gan, Fanrong Liu, Bentong Yu, Y Eugene Chin, Jian-Bin Wang
Glutamine metabolism plays an important role in cancer development and progression. Glutaminase C (GAC), the first enzyme in glutaminolysis, has emerged as an important target for cancer therapy and many studies have focused on the mechanism of enhanced GAC expression in cancer cells. However, little is known about the post-translational modification of GAC. Here, we report that phosphorylation is a crucial post-translational modification of GAC, which is responsible for the higher glutaminase activity in lung tumor tissues and cancer cells...
March 7, 2018: Cell Research
Bo Chen, Bao Zhang, Meng-Na Li, Ying Xie, Han-Qing Chen
Glutenin and gliadin were treated with protein-glutaminase in order to obtain soluble glutenin (PG-Glu) and gliadin (PG-Gli). PG-Glu or PG-Gli was added to potato starch at various concentrations (0.5%, 1.0%, and 1.5% of starch weight, w/w), and the physicochemical properties and microstructure of starch/protein mixtures were investigated. The results showed that the presence of PG-Glu or PG-Gli decreased the viscosity parameters and yield stress and consistency coefficient of mixed pastes. The starch/protein mixed pastes exhibited a pseudoplastic and shear-thinning behavior under yield stress condition, and the storage modulus and loss modulus increased...
July 1, 2018: Food Chemistry
Autumn N Harris, P Richard Grimm, Hyun-Wook Lee, Eric Delpire, Lijuan Fang, Jill W Verlander, Paul A Welling, I David Weiner
Background Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. Methods We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK)...
May 2018: Journal of the American Society of Nephrology: JASN
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