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Glutaminase

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https://www.readbyqxmd.com/read/28526749/the-origin-and-evolution-of-human-glutaminases-and-their-atypical-c-terminal-ankyrin-repeats
#1
Camila Cristina Pascoal, Zeyaul Islam, Douglas Adamoski, Igor Monteze Ferreira, Ricardo Diogo Righetto, Jefferson Bettini, Rodrigo Villares Portugal, Wyatt W Yue, Ana Gonzalez, Sandra Martha Gomes Dias, Andre Luis Berteli Ambrosio
On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals. Currently, two human genes are known to encode at least four glutaminase isoforms. However, the phylogeny of these medically relevant enzymes remains unclear, prompting us to investigate their origin and evolution. Using prokaryotic and eukaryotic glutaminase sequences, we built a phylogenetic tree whose topology suggested that the multidomain architecture was inherited from bacterial ancestors, probably simultaneously with the hosting of the proto-mitochondrion endosymbiont...
May 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28498807/knockdown-of-pkm2-and-gls1-expression-can-significantly-reverse-oxaliplatin-resistance-in-colorectal-cancer-cells
#2
Wei-Qun Lu, Ying-Ying Hu, Xiao-Ping Lin, Wei Fan
Clinical treatment for colorectal cancer (CRC) thus far encounters a huge challenge due to oxaliplatin-resistance. As crucial rate-limiting enzymes in aerobic glycolysis and glutaminolysis, pyruvate kinase M2 type (PKM2) and kidney-type glutaminase (GLS1) are proposed to carry important implications in colorectal carcinogenesis and drug-resistance. This study aimed to explore the possible association of oxaliplatin-resistance with aerobic glycolysis/glutaminolysis indexed by PKM2/GLS1 expression. PKM2 and GLS1 expression was quantified by polymerase chain reaction (PCR) and Western blot techniques in CRC cell lines...
April 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28484941/proteomics-as-a-tool-to-identify-new-targets-against-aspergillus-and-scedosporium-in-the-context-of-cystic-fibrosis
#3
Andoni Ramirez-Garcia, Aize Pellon, Idoia Buldain, Aitziber Antoran, Aitana Arbizu-Delgado, Xabier Guruceaga, Aitor Rementeria, Fernando L Hernando
Cystic fibrosis (CF) is a genetic disorder that increases the risk of suffering microbial, including fungal, infections. In this paper, proteomics-based information was collated relating to secreted and cell wall proteins with potential medical applications from the most common filamentous fungi in CF, i.e., Aspergillus and Scedosporium/Lomentospora species. Among the Aspergillus fumigatus secreted allergens, β-1,3-endoglucanase, the alkaline protease 1 (Alp1/oryzin), Asp f 2, Asp f 13/15, chitinase, chitosanase, dipeptidyl-peptidase V (DppV), the metalloprotease Asp f 5, mitogillin/Asp f 1, and thioredoxin reductase receive a special mention...
May 8, 2017: Mycopathologia
https://www.readbyqxmd.com/read/28462847/breaking-the-ritual-metabolic-cycle-in-order-to-save-acetyl-coa-a-potential-role-for-mitochondrial-humanin-in-t2-bladder-cancer-aggressiveness
#4
Nesreen Nabil Omar, Reham Fathy Tash, Youssef Shoukry, Karim Omar ElSaeed
INTRODUCTION: Cancer cells may exhibit outsourcing of their high energy need in order to avoid the intrinsic mitochondrial apoptosis. Reduced mitochondrial respiration and accumulation of mitochondrial genome mutations are among metabolic transformations in this regard. Mitochondrial humanin (MT-RNR2) is a small peptide with anti-apoptotic activities attributed to binding some pro-apoptotic proteins. AIM OF THE WORK: The current study aims at investigating the expression of mitochondrial humanin in bladder tumor cells and the possible casting of humanin anti-apoptotic action through orchestrating some of the mitochondrial metabolic enzymes...
April 24, 2017: Journal of the Egyptian National Cancer Institute
https://www.readbyqxmd.com/read/28439409/serial-deletion-reveals-structural-basis-and-stability-for-the-core-enzyme-activity-of-human-glutaminase-1-isoforms-relevance-to-excitotoxic-neurodegeneration
#5
Yuju Li, Justin Peer, Runze Zhao, Yinghua Xu, Beiqing Wu, Yi Wang, Changhai Tian, Yunlong Huang, Jialin Zheng
BACKGROUND: Glutaminase 1 is a phosphate-activated metabolic enzyme that catalyzes the first step of glutaminolysis, which converts glutamine into glutamate. Glutamate is the major neurotransmitter of excitatory synapses, executing important physiological functions in the central nervous system. There are two isoforms of glutaminase 1, KGA and GAC, both of which are generated through alternative splicing from the same gene. KGA and GAC both transcribe 1-14 exons in the N-terminal, but each has its unique C-terminal in the coding sequence...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/28427419/tnf-%C3%AE-promotes-extracellular-vesicle-release-in-mouse-astrocytes-through-glutaminase
#6
Kaizhe Wang, Ling Ye, Hongfang Lu, Huili Chen, Yanyan Zhang, Yunlong Huang, Jialin C Zheng
BACKGROUND: Extracellular vesicles (EVs) are membrane-contained vesicles shed from cells. EVs contain proteins, lipids, and nucleotides, all of which play important roles in intercellular communication. The release of EVs is known to increase during neuroinflammation. Glutaminase, a mitochondrial enzyme that converts glutamine to glutamate, has been implicated in the biogenesis of EVs. We have previously demonstrated that TNF-α promotes glutaminase expression in neurons. However, the expression and the functionality of glutaminase in astrocytes during neuroinflammation remain unknown...
April 20, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28416628/impaired-glutamatergic-neurotransmission-in-the-vmh-may-contribute-to-defective-counterregulation-in-recurrently-hypoglycemic-rats
#7
Golam M I Chowdhury, Peili Wang, Alisha Ciardi, Ramanaiah Mamillapalli, Justin Johnson, Wanling Zhu, Tore Eid, Kevin Behar, Owen Chan
The objectives of this study were to understand the role of ventromedial hypothalamic (VMH) glutamatergic neurotransmission in response to hypoglycemia and to elucidate the effects of recurrent hypoglycemia (RH) on this neurotransmitter. We measured 1) changes in interstitial VMH glutamate levels using microdialysis and biosensors, 2) identified the receptors that mediate glutamate's stimulatory effects on the counterregulatory responses, 3) quantified glutamate metabolic enzyme levels in the VMH, 4) examined astrocytic glutamate reuptake mechanisms and 5) used (1)H-[(13)C]-NMR spectroscopy to evaluate the effects of RH on neuronal glutamate metabolism...
April 17, 2017: Diabetes
https://www.readbyqxmd.com/read/28415782/glutaminase-inhibitor-cb-839-synergizes-with-carfilzomib-in-resistant-multiple-myeloma-cells
#8
Ravyn M Thompson, Dominik Dytfeld, Leticia Reyes, Reeder M Robinson, Brittany Smith, Yefim Manevich, Andrzej Jakubowiak, Mieczyslaw Komarnicki, Anna Przybylowicz-Chalecka, Tomasz Szczepaniak, Amit K Mitra, Brian G Van Ness, Magdalena Luczak, Nathan G Dolloff
Curative responses in the treatment of multiple myeloma (MM) are limited by the emergence of therapeutic resistance. To address this problem, we set out to identify druggable mechanisms that convey resistance to proteasome inhibitors (PIs; e.g., bortezomib), which are cornerstone agents in the treatment of MM. In isogenic pairs of PI sensitive and resistant cells, we observed stark differences in cellular bioenergetics between the divergent phenotypes. PI resistant cells exhibited increased mitochondrial respiration driven by glutamine as the principle fuel source...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408540/small-kernel2-encodes-a-glutaminase-in-vitamin-b6-biosynthesis-essential-for-maize-seed-development
#9
Yan-Zhuo Yang, Shuo Ding, Yong Wang, Cui-Ling Li, Yun Shen, Robert Meeley, Donald R McCarty, Bao-Cai Tan
Vitamin B6, an essential co-factor for a range of biochemical reactions and a potent antioxidant, plays important roles in plant growth, development, and stress tolerance. Vitamin B6 deficiency causes embryo lethality in Arabidopsis, but the specific role of vitamin B6 synthesis in endosperm development has not been fully addressed, especially in monocot crops where endosperm constitutes the major portion of the grain. Through molecular characterization of a small kernel2 (smk2) mutant in maize, we reveal that vitamin B6 has differential effects on embryogenesis and endosperm development in maize...
April 13, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28399896/glutaminase-1-plays-a-key-role-in-the-cell-growth-of-fibroblast-like-synoviocytes-in-rheumatoid-arthritis
#10
Soshi Takahashi, Jun Saegusa, Sho Sendo, Takaichi Okano, Kengo Akashi, Yasuhiro Irino, Akio Morinobu
BACKGROUND: The recent findings of cancer-specific metabolic changes, including increased glucose and glutamine consumption, have provided new therapeutic targets for consideration. Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. Here, we evaluated the role of these metabolic pathways in RA-FLS proliferation and in autoimmune arthritis in SKG mice...
April 11, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28396388/altering-the-allosteric-pathway-in-igps-suppresses-millisecond-motions-and-catalytic-activity
#11
George P Lisi, Kyle W East, Victor S Batista, J Patrick Loria
Imidazole glycerol phosphate synthase (IGPS) is a V-type allosteric enzyme, meaning that its catalytic rate is critically dependent on activation by its allosteric ligand, N'-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide (PRFAR). The allosteric mechanism of IGPS is reliant on millisecond conformational motions for efficient catalysis. We engineered four mutants of IGPS designed to disrupt millisecond motions and allosteric coupling to identify regions that are critical to IGPS function...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28346230/glutaminase-and-poly-adp-ribose-polymerase-inhibitors-suppress-pyrimidine-synthesis-and-vhl-deficient-renal-cancers
#12
Arimichi Okazaki, Paulo A Gameiro, Danos Christodoulou, Laura Laviollette, Meike Schneider, Frances Chaves, Anat Stemmer-Rachamimov, Stephanie A Yazinski, Richard Lee, Gregory Stephanopoulos, Lee Zou, Othon Iliopoulos
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28333400/an-improved-model-of-the-trypanosoma-brucei-ctp-synthetase-glutaminase-domain-acivicin-complex
#13
Juliana Oliveira de Souza, Alice Dawson, William N Hunter
The natural product acivicin inhibits the glutaminase activity of cytidine triphosphate (CTP) synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1-Å-resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the RCSB Protein Data Bank (PDB) and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model...
April 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28330312/isolation-and-screening-of-l-asparaginase-free-of-glutaminase-and-urease-from-fungal-sp
#14
Kruthi Doriya, Devarai Santhosh Kumar
L-Asparaginase is a chemotherapeutic drug used in the treatment of acute lymphoblastic leukaemia (ALL), a malignant disorder in children. L-Asparaginase helps in removing acrylamide found in fried and baked foods that is carcinogenic in nature. L-Asparaginase is present in plants, animals and microbes. Various microorganisms such as bacteria, yeast and fungi are generally used for the production of L-asparaginase as it is difficult to obtain the same from plants and animals. L-Asparaginase from bacteria causes anaphylaxis and other abnormal sensitive reactions due to low specificity to asparagine...
December 2016: 3 Biotech
https://www.readbyqxmd.com/read/28330094/characterization-of-antibiotic-resistant-and-enzyme-producing-bacterial-strains-isolated-from-the-arabian-sea
#15
Preeti N Tallur, Dayanand B Sajjan, Sikandar I Mulla, Manjunatha P Talwar, A Pragasam, Vinayak M Nayak, Harichandra Z Ninnekar, Shivanand S Bhat
Marine bacteria are known to produce many bioactive molecules and extracellular enzymes of commercial importance. We have investigated the bacterial diversity of the coastal area of Karwar, Karnataka State, India. Among these bacterial isolates, five bacterial strains were selected and identified by their morphological, biochemical characteristics and phylogenetic analysis based on 16S rRNA gene sequences. The identified bacterial isolates, Bacillus toyonensis PNTB1, Lysinibacillus sphaericus PTB, Vibrio vulnificus PMD, Shewanella MPTDBS, and Pseudomonas chlororaphis PNTB were characterized for their tolerance to salt and antibiotics...
June 2016: 3 Biotech
https://www.readbyqxmd.com/read/28218035/microrna-153-regulates-glutamine-metabolism-in-glioblastoma-through-targeting-glutaminase
#16
Zhenyang Liu, Junyu Wang, Yunjun Li, Juan Fan, Lihua Chen, Ruxiang Xu
Glioblastoma is the most aggressive manifestation of malignant gliomas and considered to be among the deadliest forms of human cancers. MicroRNAs are found to tightly regulate diverse biological processes and considered to play important roles in cancer etiology. In this study, we found that microRNA-153 was significantly downregulated in glioblastoma tissues compared to matched non-tumor tissues and in glioblastoma cell lines. To investigate the potential function of microRNA-153 in glioblastoma, we transfected glioblastoma cell line U87MG as well as U373MG with synthetic microRNA-153 oligos and observed decreased cell proliferation and increased apoptosis...
February 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28208301/biomolecular-interaction-assays-identified-dual-inhibitors-of-glutaminase-and-glutamate-dehydrogenase-that-disrupt-mitochondrial-function-and-prevent-growth-of-cancer-cells
#17
Min Zhu, Jinzhang Fang, Jingjing Zhang, Zheng Zhang, Jianhui Xie, Yan Yu, Jennifer Jin Ruan, Zhao Chen, Wei Hou, Gensheng Yang, Weike Su, Benfang Helen Ruan
Glutaminase (KGA/isoenzyme GAC) is an emerging and important drug target for cancer. Traditional methods for assaying glutaminase activity are coupled with several other enzymes. Such coupled assays do not permit the direct and stringent characterization of specific glutaminase inhibitors. Ebselen was identified as a potent 9 nM KGA inhibitor in the KGA/glutamate oxidase (GO)/horse radish peroxidase (HRP) coupled assay but showed very weak activity in inhibiting the growth of glutamine-dependent cancer cells...
February 7, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28205049/construction-of-potent-recombinant-strain-through-intergeneric-protoplast-fusion-in-endophytic-fungi-for-anticancerous-enzymes-production-using-rice-straw
#18
Mervat Morsy Abbas Ahmed El-Gendy, Salha Hassan Mastour Al-Zahrani, Ahmed Mohamed Ahmed El-Bondkly
Among all fungal endophytes isolates derived from different ethno-medical plants, the hyper-yield L-asparaginase and L-glutaminase wild strains Trichoderma sp. Gen 9 and Cladosporium sp. Gen 20 using rice straw under solid-state fermentation (SSF) were selected. The selected strains were used as parents for the intergeneric protoplast fusion program to construct recombinant strain for prompt improvement production of these enzymes in one recombinant strain. Among 21 fusants obtained, the recombinant strain AYA 20-1, with 2...
February 15, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28202527/-18-f-2s-4r-4-fluoroglutamine-pet-detects-glutamine-pool-size-changes-in-triple-negative-breast-cancer-in-response-to-glutaminase-inhibition
#19
Rong Zhou, Austin R Pantel, Shihong Li, Brian P Lieberman, Karl Ploessl, Hoon Choi, Eric Blankemeyer, Hsiaoju Lee, Hank F Kung, Robert H Mach, David A Mankoff
Glutaminolysis is a metabolic pathway adapted by many aggressive cancers, including triple-negative breast cancers (TNBC), to utilize glutamine for survival and growth. In this study, we examined the utility of [(18)F](2S,4R)4-fluoroglutamine ([(18)F]4F-Gln) PET to measure tumor cellular glutamine pool size, whose change might reveal the pharmacodynamic (PD) effect of drugs targeting this cancer-specific metabolic pathway. High glutaminase (GLS) activity in TNBC tumors resulted in low cellular glutamine pool size assayed via high-resolution (1)H magnetic resonance spectroscopy (MRS)...
March 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28196863/conformational-changes-in-the-activation-loop-of-mitochondrial-glutaminase-c-a-direct-fluorescence-readout-that-distinguishes-the-binding-of-allosteric-inhibitors-from-activators
#20
Clint A Stalnecker, Jon W Erickson, Richard A Cerione
The first step in glutamine catabolism is catalysis by the mitochondrial enzyme glutaminase, with a specific isoform, glutaminase C (GAC), being highly expressed in cancer cells. GAC activation requires the formation of homotetramers, promoted by anionic allosteric activators such as inorganic phosphate. This leads to the proper orientation of a flexible loop proximal to the dimer-dimer interface that is essential for catalysis (i.e. the "activation loop"). A major class of allosteric inhibitors of GAC, with the prototype being bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and the related molecule CB-839, binds to the activation loop and induces the formation of an inactive tetramer (two inhibitors bound per active tetramer)...
April 14, 2017: Journal of Biological Chemistry
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