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2 hydroxyglutarate

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https://www.readbyqxmd.com/read/28053877/metabolomic-analysis-identifies-differentially-produced-oral-metabolites-including-the-oncometabolite-2-hydroxyglutarate-in-patients-with-head-and-neck-squamous-cell-carcinoma
#1
Pranab K Mukherjee, Pauline Funchain, Mauricio Retuerto, Richard J Jurevic, Nicole Fowler, Brian Burkey, Charis Eng, Mahmoud A Ghannoum
BACKGROUND: Metabolomics represents a promising approach for discovering novel targets and biomarkers in head and neck squamous cell carcinoma (HNSCC). Here we used metabolomics to identify oral metabolites associated with HNSCC. METHODS: Tumor and adjacent normal tissue from surgical resections and presurgical oral washes as well as oral washes were collected from healthy participants. Metabolites extractions of these samples were analyzed by liquid chromatography-mass spectroscopy (LC/MS), LC/MS/MS and gas chromatography-MS (GC/MS)...
June 2017: BBA Clinical
https://www.readbyqxmd.com/read/28052098/idh1-r132h-mutation-enhances-cell-migration-by-activating-akt-mtor-signaling-pathway-but-sensitizes-cells-to-5-fu-treatment-as-nadph-and-gsh-are-reduced
#2
Huixia Zhu, Ye Zhang, Jianfeng Chen, Jiangdong Qiu, Keting Huang, Mindan Wu, Chunlin Xia
AIM OF STUDY: Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. MATERIALS AND METHODS: Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively...
2017: PloS One
https://www.readbyqxmd.com/read/27982681/background-levels-of-neomorphic-2-hydroxyglutarate-facilitate-proliferation-of-primary-fibroblasts
#3
A Dvořák, J Zelenka, K Smolková, L Vítek, P JeŽek
Each cell types or tissues contain certain "physiological" levels of R-2-hydroxyglutarate (2HG), as well as enzymes for its synthesis and degradation. 2HG accumulates in certain tumors, possessing heterozygous point mutations of isocitrate dehydrogenases IDH1 (cytosolic) or IDH2 (mitochondrial) and contributes to strengthening their malignancy by inhibiting 2-oxoglutarate-dependent dioxygenases. By blocking histone de-methylation and 5-methyl-cytosine hydroxylation, 2HG maintains cancer cells de-differentiated and promotes their proliferation...
December 16, 2016: Physiological Research
https://www.readbyqxmd.com/read/27956631/the-idh2-r172k-mutation-associated-with-angioimmunoblastic-t-cell-lymphoma-produces-2hg-in-t-cells-and-impacts-lymphoid-development
#4
François Lemonnier, Rob A Cairns, Satoshi Inoue, Wanda Y Li, Aurélie Dupuy, Sophie Broutin, Nadine Martin, Virginie Fataccioli, Romain Pelletier, Andrew Wakeham, Bryan E Snow, Laurence de Leval, Anais Pujals, Corinne Haioun, Angelo Paci, Erica R Tobin, Rohini Narayanaswamy, Katherine Yen, Shengfang Jin, Philippe Gaulard, Tak W Mak
Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27923773/mitochondrial-protein-lipoylation-and-the-2-oxoglutarate-dehydrogenase-complex-controls-hif1%C3%AE-stability-in-aerobic-conditions
#5
Stephen P Burr, Ana S H Costa, Guinevere L Grice, Richard T Timms, Ian T Lobb, Peter Freisinger, Roger B Dodd, Gordon Dougan, Paul J Lehner, Christian Frezza, James A Nathan
Hypoxia-inducible transcription factors (HIFs) control adaptation to low oxygen environments by activating genes involved in metabolism, angiogenesis, and redox homeostasis. The finding that HIFs are also regulated by small molecule metabolites highlights the need to understand the complexity of their cellular regulation. Here we use a forward genetic screen in near-haploid human cells to identify genes that stabilize HIFs under aerobic conditions. We identify two mitochondrial genes, oxoglutarate dehydrogenase (OGDH) and lipoic acid synthase (LIAS), which when mutated stabilize HIF1α in a non-hydroxylated form...
November 8, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27885126/why-is-l-2-hydroxyglutaric-aciduria-relevant-for-a-general-practitioner
#6
Marlies Bohm
No abstract text is available yet for this article.
November 26, 2016: Veterinary Record
https://www.readbyqxmd.com/read/27856334/quantitative-metabolic-flux-analysis-reveals-an-unconventional-pathway-of-fatty-acid-synthesis-in-cancer-cells-deficient-for-the-mitochondrial-citrate-transport-protein
#7
Lei Jiang, Adam Boufersaoui, Chendong Yang, Bookyung Ko, Dinesh Rakheja, Gerardo Guevara, Zeping Hu, Ralph J DeBerardinis
The mitochondrial citrate transport protein (CTP), encoded by SLC25A1, accommodates bidirectional trafficking of citrate between the mitochondria and cytosol, supporting lipid biosynthesis and redox homeostasis. Genetic CTP deficiency causes a fatal neurodevelopmental syndrome associated with the accumulation of L- and D-2-hydroxyglutaric acid, and elevated CTP expression is associated with poor prognosis in several types of cancer, emphasizing the importance of this transporter in multiple human pathologies...
November 14, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27852048/igfbp2-expression-predicts-idh-mutant-glioma-patient-survival
#8
L Eric Huang, Adam L Cohen, Howard Colman, Randy L Jensen, Daniel W Fults, William T Couldwell
Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas...
November 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27847299/an-mrspec-database-query-and-visualization-engine-with-applications-as-a-clinical-diagnostic-and-research-tool
#9
Filip Miscevic, Justin Foong, Benjamin Schmitt, Susan Blaser, Michael Brudno, Andreas Schulze
PURPOSE: Proton magnetic resonance spectroscopy (MRspec), one of the very few techniques for in vivo assessment of neuro-metabolic profiles, is often complicated by lack of standard population norms and paucity of computational tools. METHODS: 7035 scans and clinical information from 4430 pediatric patients were collected from 2008 to 2014. Scans were conducted using a 1.5T (n=3664) or 3T scanner (n=3371), and with either a long (144ms, n=5559) or short echo time (35ms, n=1476)...
December 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27836888/s-2-hydroxyglutarate-maintains-a-proliferative-cd8-t-cell-state
#10
(no author information available yet)
S-2HG acts as an immunometabolite to regulate CD8(+) T cell fate, promoting persistence and survival.
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27834880/double-intramolecular-transacetalization-of-polyhydroxy-acetals-synthesis-of-conformationally-restricted-1-3-dioxanes-with-axially-oriented-phenyl-moiety
#11
Samuel Asare-Nkansah, Bernhard Wünsch
The synthesis of conformationally-restricted 1,3-dioxanes with a phenyl moiety fixed in an axial orientation at the acetalic center is described. Starting with diethyl 3-hydroxyglutarate (15), benzaldehyde acetal 12a and acetophenone ketal 12b bearing a protected 1,3,5-trihydroxypentyl side chain in the o-position were prepared. The first acid-catalyzed intramolecular transacetalization gave a mixture of diastereomeric 2-benzofurans 18 (ratio of diastereomers 2:2:1:1). After OH group deprotection, the second intramolecular transacetalization afforded tricyclic alcohol 14a (2-(1,5-epoxy-1,3,4,5-tetrahydro-2-benzoxepin-3-yl]ethan-1-ol)...
November 9, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27824159/oncometabolite-d-2-hydroxyglurate-directly-induces-epithelial-mesenchymal-transition-and-is-associated-with-distant-metastasis-in-colorectal-cancer
#12
Hugh Colvin, Naohiro Nishida, Masamitsu Konno, Naotsugu Haraguchi, Hidekazu Takahashi, Junichi Nishimura, Taishi Hata, Koichi Kawamoto, Ayumu Asai, Kenta Tsunekuni, Jun Koseki, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Deranged metabolism is a hallmark of cancer, playing a significant role in driving the disease process. One such example is the induction of carcinogenesis by the oncometabolite D-2 hydroxyglutarate (D-2HG), which is produced by the mutated enzyme isocitrate dehydrogenase (IDH) occurring in subsets of leukaemias and brain tumours. The oncogenic property of D-2HG appears to stem from its ability to interfere with the activities of α-ketoglutarate-dependent dioxygenases, including the Jumonji family histone demethylases...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27806325/inhibiting-glutaminase-in-acute-myeloid-leukemia-metabolic-dependency-of-selected-aml-subtypes
#13
Polina Matre, Juliana Velez, Rodrigo Jacamo, Yuan Qi, Xiaoping Su, Tianyu Cai, Steven M Chan, Alessia Lodi, Shannon R Sweeney, Helen Ma, Richard Eric Davis, Natalia Baran, Torsten Haferlach, Xiaohua Su, Elsa Renee Flores, Doriann Gonzalez, Sergej Konoplev, Ismael Samudio, Courtney DiNardo, Ravi Majeti, Aaron D Schimmer, Weiqun Li, Taotao Wang, Stefano Tiziani, Marina Konopleva
Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC)...
October 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27798602/s-2-hydroxyglutarate-regulates-cd8-t-lymphocyte-fate
#14
Petros A Tyrakis, Asis Palazon, David Macias, Kian L Lee, Anthony T Phan, Pedro Veliça, Jia You, Grace S Chia, Jingwei Sim, Andrew Doedens, Alice Abelanet, Colin E Evans, John R Griffiths, Lorenz Poellinger, Ananda W Goldrath, Randall S Johnson
R-2-hydroxyglutarate accumulates to millimolar levels in cancer cells with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both metabolite enantiomers, R- and S-2-hydroxyglutarate, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that 2-hydroxyglutarate accumulates in mouse CD8(+) T cells in response to T-cell receptor triggering, and accumulates to millimolar levels in physiological oxygen conditions through a hypoxia-inducible factor 1-alpha (HIF-1α)-dependent mechanism...
December 8, 2016: Nature
https://www.readbyqxmd.com/read/27790731/metabolomics-analysis-revealed-distinct-cyclic-changes-of-metabolites-altered-by-chronic-ethanol-plus-binge-and-shp-deficiency
#15
Melanie Tran, Zhihong Yang, Suthat Liangpunsakul, Li Wang
BACKGROUND: Chronic ethanol (EtOH) consumption causes alcoholic liver disease (ALD), and disruption of the circadian system facilitates the development of ALD. Small heterodimer partner (SHP) is a nuclear receptor and critical regulator of hepatic lipid metabolism. This study aimed at depicting circadian metabolomes altered by chronic EtOH-plus-binge and Shp deficiency using high-throughput metabolomics. METHODS: Wild-type (WT) C57BL/6 and Shp(-/-) mice were fed the control diet (CD) or Lieber-DeCarli EtOH liquid diet (ED) for 10 days followed by a single bout of maltose (CD + M) or EtOH (ED + E) binge on the 11th day...
December 2016: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/27781195/intracerebral-distribution-of-the-oncometabolite-d-2-hydroxyglutarate-in-mice-bearing-mutant-isocitrate-dehydrogenase-brain-tumors-implications-for-tumorigenesis
#16
Amanda J Pickard, Albert S W Sohn, Thomas F Bartenstein, Shan He, Yi Zhang, James M Gallo
The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis - providing D2HG interstitial fluid concentrations - sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27774134/discovery-of-8-membered-ring-sulfonamides-as-inhibitors-of-oncogenic-mutant-isocitrate-dehydrogenase-1
#17
Jason M Law, Sebastian C Stark, Ke Liu, Norah E Liang, Mahmud M Hussain, Matthias Leiendecker, Daisuke Ito, Oscar Verho, Andrew M Stern, Stephen E Johnston, Yan-Ling Zhang, Gavin P Dunn, Alykhan F Shamji, Stuart L Schreiber
Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27760377/therapeutic-relevance-of-mtor-inhibition-in-murine-succinate-semialdehyde-dehydrogenase-deficiency-ssadhd-a-disorder-of-gaba-metabolism
#18
K R Vogel, G R Ainslie, E E W Jansen, G S Salomons, K M Gibson
Aldehyde dehydrogenase 5a1-deficient (aldh5a1(-/-)) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis that aldh5a1(-/-) mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR...
January 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27758882/mutant-idh1-expression-drives-tert-promoter-reactivation-as-part-of-the-cellular-transformation-process
#19
Shigeo Ohba, Joydeep Mukherjee, Tor-Christian Johannessen, Andrew Mancini, Tracy T Chow, Matthew Wood, Lindsey Jones, Tali Mazor, Roxanne E Marshall, Pavithra Viswanath, Kyle M Walsh, Arie Perry, Robert J A Bell, Joanna J Phillips, Joseph F Costello, Sabrina M Ronen, Russell O Pieper
Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1(mut)) genes as they progressed through their lifespan...
October 6, 2016: Cancer Research
https://www.readbyqxmd.com/read/27729589/clinical-features-and-disease-progression-of-l-2-hydroxyglutaric-aciduria-in-27-staffordshire-bull-terriers
#20
A Shea, L De Risio, H Carruthers, A Ekiri, E Beltran
To describe the development of clinical signs (CS) and outcome of L-2-hydroxyglutaric aciduria (L-2-HGA), owners of 119 Staffordshire bull terriers positive for the known L-2-hydroxyglutarate dehydrogenase autosomal-recessive mutations were requested to complete a questionnaire regarding their pet's CS. Questionnaires were returned for 27 dogs, all with neurological abnormalities-not all questions were answered in all cases. The mean age of CS onset was 12 months (range 2.5-60). Gait dysfunction was reported in 26/26 dogs, with stiffness of all four limbs the most common (24/26) and earliest recognised abnormality...
October 11, 2016: Veterinary Record
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