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Glutaminase

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https://www.readbyqxmd.com/read/29158920/enhancement-in-tonically-active-glutamatergic-inputs-to-the-rostral-ventrolateral-medulla-contributes-to-neuropathic-pain-induced-high-blood-pressure
#1
Wei Wang, Zui Zou, Xing Tan, Ru-Wen Zhang, Chang-Zhen Ren, Xue-Ya Yao, Cheng-Bao Li, Wei-Zhong Wang, Xue-Yin Shi
Neuropathic pain increases the risk of cardiovascular diseases including hypertension with the characteristic of sympathetic overactivity. The enhanced tonically active glutamatergic input to the rostral ventrolateral medulla (RVLM) contributes to sympathetic overactivity and blood pressure (BP) in cardiovascular diseases. We hypothesize that neuropathic pain enhances tonically active glutamatergic inputs to the RVLM, which contributes to high level of BP and sympathetic outflow. Animal model with the trigeminal neuropathic pain was induced by the infraorbital nerve-chronic constriction injury (ION-CCI)...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/29156762/glutaminase-inhibition-in-multiple-myeloma-induces-apoptosis-via-myc-degradation
#2
Madlen Effenberger, Kathryn S Bommert, Viktoria Kunz, Jessica Kruk, Ellen Leich, Martina Rudelius, Ralf Bargou, Kurt Bommert
Multiple Myeloma (MM) is an incurable hematological malignancy affecting millions of people worldwide. As in all tumor cells both glucose and more recently glutamine have been identified as important for MM cellular metabolism, however there is some dispute as to the role of glutamine in MM cell survival. Here we show that the small molecule inhibitor compound 968 effectively inhibits glutaminase and that this inhibition induces apoptosis in both human multiple myeloma cell lines (HMCLs) and primary patient material...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29119293/asparaginase-erwinia-chrysanthemi-effectively-depletes-plasma-glutamine-in-adult-patients-with-relapsed-refractory-acute-myeloid-leukemia
#3
Ashkan Emadi, Jennie Y Law, Erin T Strovel, Rena G Lapidus, Linda J B Jeng, Myounghee Lee, Miriam G Blitzer, Brandon A Carter-Cooper, Danielle Sewell, Isabella Van Der Merwe, Sunita Philip, Mohammad Imran, Stephen L Yu, Hongxia Li, Philip C Amrein, Vu H Duong, Edward A Sausville, Maria R Baer, Amir T Fathi, Zeba Singh, Søren M Bentzen
Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 μmol/L in patients with relapsed or refractory (R/R) AML...
November 8, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29111704/new-method-to-produce-kokumi-seasoning-from-protein-hydrolysates-using-bacterial-enzymes
#4
Hideyuki Suzuki, Yuko Nakafuji, Tomoki Tamura
In the present study, we demonstrate a novel use for a commercially available glutaminase that can be used as a γ-glutamyltranspeptidase in kokumi seasoning production. Soy protein and gluten were hydrolyzed using a protease isolated from Bacillus licheniformis. The resulting protein hydrolysates were γ-glutamylated with a γ-glutamyltranspeptidase, which is sold as a glutaminase from Bacillus amyloliquefaciens, to produce kokumi seasonings. For γ-glutamylation of soy protein hydrolysate, glutamine was added to the reaction mixture...
November 17, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29108742/gene-expression-analysis-reveals-chronic-low-level-exposure-to-the-pesticide-diazinon-affects-psychological-disorders-gene-sets-in-the-adult-rat
#5
Claire Y Savy, Ann E Fitchett, Peter G Blain, Christopher M Morris, Sarah J Judge
Chronic low level exposure to organophosphate (OPs) pesticides in adulthood has been linked to adverse neurobehavioural deficits and psychological disorder symptoms, although this remains a contentious issue. The OP-induced biological changes that could underlie these effects are unclear. We assessed gene expression changes following chronic low level exposure to diazinon, a pesticide with a high dietary exposure risk. Adult male rats were orally exposed to diazinon (0, 1, 2mg/kg, 5days a week for 12 weeks)...
November 3, 2017: Toxicology
https://www.readbyqxmd.com/read/29107960/glutamine-deficiency-induces-dna-alkylation-damage-and-sensitizes-cancer-cells-to-alkylating-agents-through-inhibition-of-alkbh-enzymes
#6
Thai Q Tran, Mari B Ishak Gabra, Xazmin H Lowman, Ying Yang, Michael A Reid, Min Pan, Timothy R O'Connor, Mei Kong
Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death...
November 2017: PLoS Biology
https://www.readbyqxmd.com/read/29101342/a-protease-resistant-escherichia-coli-asparaginase-with-outstanding-stability-and-enhanced-anti-leukaemic-activity-in-vitro
#7
Maristella Maggi, Steven D Mittelman, Jean Hugues Parmentier, Giorgio Colombo, Massimiliano Meli, Jeannette Marie Whitmire, D Scott Merrell, Julian Whitelegge, Claudia Scotti
L-Asparaginases (ASNases) have been used as first line drugs for paediatric Acute Lymphoblastic Leukaemia (ALL) treatment for more than 40 years. Both the Escherichia coli (EcAII) and Erwinia chrysanthemi (ErAII) type II ASNases currently used in the clinics are characterized by high in vivo instability, short half-life and the requirement of several administrations to obtain a pharmacologically active concentration. Moreover, they are sensitive to proteases (cathepsin B and asparagine endopeptidase) that are over-expressed by resistant leukaemia lymphoblasts, thereby impairing drug activity and pharmacokinetics...
November 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29097210/mir-137-inhibits-glutamine-catabolism-and-growth-of-malignant-melanoma-by-targeting-glutaminase
#8
Wenkang Luan, Zhou Zhou, Yan Zhu, Yun Xia, Jinlong Wang, Bin Xu
Glutamine catabolism is considered to be an important metabolic pathway for cancer cells. Glutaminase (GLS) is the important rate-limiting enzyme of glutamine catabolism. miR-137 functions as a tumor suppressor in many human malignant tumors. However, the role and molecular mechanism of miR-137 and GLS in malignant melanoma has not been reported. In this study, we showed that miR-137 was decreased in melanoma tissue, and the low miR-137 level and high GLS expression are independent risk factor in melanoma. miR-137 suppressed the proliferation and glutamine catabolism of melanoma cells...
October 30, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29095161/structure-and-function-of-the-thermostable-l-asparaginase-from-thermococcus-kodakarensis
#9
Jingxu Guo, Alun R Coker, Steve P Wood, Jonathan B Cooper, Shahid Mahmood Chohan, Naeem Rashid, Muhummad Akhtar
L-Asparaginases catalyse the hydrolysis of asparagine to aspartic acid and ammonia. In addition, L-asparaginase is involved in the biosynthesis of amino acids such as lysine, methionine and threonine. These enzymes have been used as chemotherapeutic agents for the treatment of acute lymphoblastic leukaemia and other haematopoietic malignancies since the tumour cells cannot synthesize sufficient L-asparagine and are thus killed by deprivation of this amino acid. L-Asparaginases are also used in the food industry and have potential in the development of biosensors, for example for asparagine levels in leukaemia...
November 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/29077094/non-oncogenic-roles-of-tap73-from-multiciliogenesis-to-metabolism
#10
REVIEW
Alice Nemajerova, Ivano Amelio, Jakob Gebel, Volker Dötsch, Gerry Melino, Ute M Moll
The p53 family of transcription factors (p53, p63 and p73) covers a wide range of functions critical for development, homeostasis and health of mammals across their lifespan. Beside the well-established tumor suppressor role, recent evidence has highlighted novel non-oncogenic functions exerted by p73. In particular, p73 is required for multiciliated cell (MCC) differentiation; MCCs have critical roles in brain and airways to move fluids across epithelial surfaces and to transport germ cells in the reproductive tract...
October 27, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29072450/ebselen-mechanisms-of-glutamate-dehydrogenase-and-glutaminase-enzyme-inhibition
#11
Yan Yu, Yanhong Jin, Jie Zhou, Haoqiang Ruan, Han Zhao, Shiying Lu, Yue Zhang, Di Li, Xiaoyun Ji, Benfang Helen Ruan
Ebselen modulates target proteins through redox reactions with selenocysteine/cysteine residues, or through binding to the zinc finger domains. However, a recent contradiction in ebselen inhibition of kidney type glutaminase (KGA) stimulated our interest in investigating its inhibition mechanism with glutamate dehydrogenase (GDH), KGA, thioredoxin reductase (TrxR), and glutathione S-transferase. Fluorescein- or biotin-labeled ebselen derivatives were synthesized for mechanistic analyses. Biomolecular interaction analyses showed that only GDH, KGA, and TrxR proteins can bind to the ebselen derivative, and the binding to GDH and KGA could be competed off by glutamine or glutamate...
November 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29070466/-rhoa-rho-kinase-contributes-to-chronic-pain-following-thoracotomy-by-up-regulating-glutaminase-1-expression-in-rat-spinal-dorsal-cord
#12
Zi-Yan Liu, Hai-Tang Wang, Jing Tang, Zai-Sheng Qin
OBJECTIVE: To investigate whether RhoA/Rho-kinase contributes to the occurrence of chronic post-thoracotomy pain (CPSP) by up regulation of glutaminase 1 (GLS1) expression in the spinal dorsal cord. METHODS: Twenty five male Sprague Dawley (SD) rats were divided into control group (n=5) and model group (n=20). The rats in the model group were randomized into two sub groups (n=10) for observation on day 10 and day 21 after thoracotomy, and each group was further divided into CPSP and non CPSP groups according to the behavioral test results...
October 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/29032577/pyruvate-kinase-isozymes-m2-and-glutaminase-might-be-promising-molecular-targets-for-the-treatment-of-gastric-cancer
#13
Kishu Kitayama, Masakazu Yashiro, Tamami Morisaki, Yuichiro Miki, Tomohisa Okuno, Haruhito Kinoshita, Tatsunari Fukuoka, Hiroaki Kasashima, Go Masuda, Tsuyoshi Hasegawa, Katsunobu Sakurai, Naoshi Kubo, Kosei HIrakawa, Masaichi Ohira
The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and 4 parent cell lines were used. RT-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: pyruvate kinase isozymes M2 (PKM2), glutaminase (GLS), enolase 1 (ENO1), glucose-6-phosphate dehydrogenase (G6PDH), and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, Shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo...
October 15, 2017: Cancer Science
https://www.readbyqxmd.com/read/29029014/1-25-dihydroxyvitamin-d-regulation-of-glutamine-synthetase-and-glutamine-metabolism-in-human-mammary-epithelial-cells
#14
Sarah Beaudin, JoEllen Welsh
Genomic profiling has identified a subset of metabolic genes that are altered by 1,25-dihydroxyvitamin D (1,25D) in breast cells including GLUL, the gene that encodes glutamine synthetase (GS). Here, we explored the relevance of vitamin D modulation of GLUL and other metabolic genes in the context of glutamine utilization and dependence. We show that exposure of breast epithelial cells to glutamine deprivation or a GS inhibitor reduced growth and these effects were exacerbated by co-treatment with 1,25D. 1,25D down-regulation of GLUL was sufficient to reduce abundance and activity of GS...
September 28, 2017: Endocrinology
https://www.readbyqxmd.com/read/29021138/glutamine-addiction-in-kidney-cancer-suppresses-oxidative-stress-and-can-be-exploited-for-real-time-imaging
#15
Omran Abu Aboud, Samy L Habib, Josephine F Trott, Benjamin Stewart, Sitai Liang, Abhijit J Chaudhari, Julie L Sutcliffe, Robert H Weiss
Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species (ROS) and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared to adjacent normal tissue and the contralateral kidney...
October 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29019707/glutaminolysis-promotes-collagen-translation-and-stability-via-%C3%AE-ketoglutarate-mediated-mtor-activation-and-proline-hydroxylation
#16
Jing Ge, Huachun Cui, Na Xie, Sami Banerjee, Sijia Guo, Shubham Dubey, Stephen Barnes, Gang Liu
Glutaminolysis is the metabolic process of glutamine, of which aberration has been implicated in several pathogeneses. While we and others recently found a diversity of metabolic dysregulations in organ fibrosis, it is unknown if glutaminolysis regulates the pro-fibrotic activities of myofibroblasts, the primary effector in this pathology. In this study, we found that lung myofibroblasts demonstrated significantly augmented glutaminolysis that was mediated by elevated Glutaminase 1 (Gls1). Inhibition of glutaminolysis by specific Gls1 inhibitors CB-839 and BPTES as well as Gls1 siRNA blunted the expression of collagens, but not that of Fibronectin, Elastin or myofibroblastic marker smooth muscle actin α (SMA-α)...
October 11, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28993139/rapid-quantification-of-glutaminase-2-gls2-related-metabolites-by-hilic-ms-ms
#17
Guan-Yuan Chen, Hsi-Chun Chao, Hsiao-Wei Liao, I-Lin Tsai, Ching-Hua Kuo
Glutamine, glutamate and glutathione are key modulators of excessive oxidative stress in tumor cells. In this study, we developed a rapid and accurate HILIC-MS/MS method to simultaneously determine concentrations of cellular glutamine, glutamate and glutathione. A bared silica HILIC column was employed to analyze these polar metabolites. The LC-MS parameters were optimized to achieve high sensitivity and selectivity. The analysis can be completed within 4 min under optimal conditions. The method was validated in terms of accuracy, precision, and linearity...
October 6, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/28992545/downregulation-of-sirt2-inhibits-invasion-of-hepatocellular-carcinoma-by-inhibiting-energy-metabolism
#18
Shan Huang, Zhenguo Zhao, Dehua Tang, Qian Zhou, Yang Li, Lixing Zhou, Yuyao Yin, Yuming Wang, Yida Pan, Robert Gregory Dorfman, Tingsheng Ling, Mingming Zhang
Hepatocellular carcinoma (HCC) is one of the most common neoplasms, and metastasis is the most important feature for HCC-related deaths. Mounting evidence implies the dynamic regulatory role of SIRT2, a histone deacetylase, in cancer cells. Unfortunately, the role of SIRT2 and the antitumor activity of its inhibition are not known in HCC. The present study aims to evaluate the biological function of SIRT2 in HCC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival...
December 2017: Translational Oncology
https://www.readbyqxmd.com/read/28987935/in-situ-measurements-of-mitochondrial-matrix-enzyme-activities-using-plasma-and-mitochondrial-membrane-permeabilization-agents
#19
Ajit S Divakaruni, Alexander Y Andreyev, George W Rogers, Anne N Murphy
Activities of enzymes localized to the mitochondrial matrix of mammalian cells are often critical regulatory steps in cellular metabolism. As such, measurement of matrix enzyme activities in response to genetic modifications or drug interventions is often desired. However, measurements in intact cells are often hampered by the presence of other isozymes in the cytoplasm as well as the inability to deliver enzyme substrates across cellular membranes. Classic approaches to liberate matrix enzymes utilize harsh treatments that disrupt intracellular architecture or require significant starting material to allow mitochondrial isolation prior to sample extraction...
October 4, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/28978620/de-novo-myc-addiction-as-an-adaptive-response-of-cancer-cells-to-cdk4-6-inhibition
#20
Míriam Tarrado-Castellarnau, Pedro de Atauri, Josep Tarragó-Celada, Jordi Perarnau, Mariia Yuneva, Timothy M Thomson, Marta Cascante
Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF-1α-mediated responses to hypoxia...
October 4, 2017: Molecular Systems Biology
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