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2 hydroxyglutarate

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https://www.readbyqxmd.com/read/28193778/ag-221-a-first-in-class-therapy-targeting-acute-myeloid-leukemia-harboring-oncogenic-idh2-mutations
#1
Katharine Yen, Jeremy Travins, Fang Wang, Muriel D David, Erin Artin, Kim Straley, Anil Padyana, Stefan Gross, Byron DeLaBarre, Erica Tobin, Yue Chen, Raj Nagaraja, Sung Choe, Lei Jin, Zenon Konteatis, Giovanni Cianchetta, Jeffrey O Saunders, Francesco G Salituro, Cyril Quivoron, Paule Opolon, Olivia Bawa, Véronique Saada, Angelo Paci, Sophie Broutin, Olivier A Bernard, Stéphane de Botton, Benoît S Marteyn, Monika Pilichowska, YingXia Xu, Cheng Fang, Fan Jiang, Wentao Wei, Shengfang Jin, Lee Silverman, Wei Liu, Hua Yang, Lenny Dang, Marion Dorsch, Virginie Penard-Lacronique, Scott A Biller, Shin-San Michael Su
Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite, (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the Tet family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach...
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28173805/serum-proteomic-profiles-in-ckcs-with-mitral-valve-disease
#2
Chiara Locatelli, Cristian Piras, Giulia Riscazzi, Isabella Alloggio, Ilaria Spalla, Alessio Soggiu, Viviana Greco, Luigi Bonizzi, Paola Roncada, Paola G Brambilla
BACKGROUND: Myxomatous mitral valve disease (MVD) is the most common acquired heart disease in dogs, and the Cavalier King Charles Spaniel (CKCS) is the most studied breed because of the high prevalence, early onset and hereditary component evidenced in the breed. MVD has different severity levels, and there are many practical limitations in identifying its asymptomatic stages. Proteomic techniques are valuable for studying the proteins and peptides involved in cardiovascular diseases, including the period prior to the clinical onset of the disease...
February 7, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28150876/edited-1-h-magnetic-resonance-spectroscopy-in-vivo-methods-and-metabolites
#3
REVIEW
Ashley D Harris, Muhammad G Saleh, Richard A E Edden
The Proton magnetic resonance ((1) H-MRS) spectrum contains information about the concentration of tissue metabolites within a predefined region of interest (a voxel). The conventional spectrum in some cases obscures information about less abundant metabolites due to limited separation and complex splitting of the metabolite peaks. One method to detect these metabolites is to reduce the complexity of the spectrum using editing. This review provides an overview of the one-dimensional editing methods available to interrogate these obscured metabolite peaks...
February 2, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/28148839/2-hydroxyglutarate-produced-by-neomorphic-idh-mutations-suppresses-homologous-recombination-and-induces-parp-inhibitor-sensitivity
#4
Parker L Sulkowski, Christopher D Corso, Nathaniel D Robinson, Susan E Scanlon, Karin R Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini K Sundaram, Denise C Hegan, Nathan R Fons, Gregory A Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk M De Feyter, Robin A de Graaf, Yulia V Surovtseva, Maureen Kachman, Stephanie Halene, Murat Günel, Peter M Glazer, Ranjit S Bindra
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28148827/mutant-idh1-disrupts-the-mouse-subventricular-zone-and-alters-brain-tumor-progression
#5
Christopher J Pirozzi, Austin B Carpenter, Matthew S Waitkus, Catherine Y Wang, Huishan Zhu, Landon J Hansen, Lee H Chen, Paula K Greer, Jie Feng, Yu Wang, Cheryl B Bock, Ping Fan, Ivan Spasojevic, Roger E McLendon, Darell D Bigner, Yiping He, Hai Yan
: IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell cycle arrest as well as a decreased ability to undergo neuronal differentiation...
February 1, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28141777/an-l-2-hydroxyglutaric-aciduria-case-presented-with-acute-bacterial-meningitis
#6
Sedat Işikay, Nurgül Işikay, Serkan Kirik, Olcay Güngör
No abstract text is available yet for this article.
February 2017: Pediatric Emergency Care
https://www.readbyqxmd.com/read/28139228/chiral-separation-of-short-chain-aliphatic-hydroxycarboxylic-acids-on-cinchonan-carbamate-based-weak-chiral-anion-exchangers-and-zwitterionic-chiral-ion-exchangers
#7
Carlos Calderón, Michael Lämmerhofer
Chiral short chain aliphatic hydrocarboxylic acids (HCAs) are common compounds being part of different biological processes. In order to control and understand these processes is of pivotal importance to determine the identity of the involved enantiomer or their enantiomeric ratio. In this study the capacity of quinine- and quinidine-derived chiral stationary phases to perform the enantioseparation of eight chiral HCAs (tartaric acid, isocitric acid, malic acid, glyceric acid, 2-hydroxyglutaric acid, 2-hydroxybutyric acid, lactic acid and 3-hydroxybutyric acid) was evaluated...
March 3, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28137912/l2hgdh-deficiency-accumulates-l-2-hydroxyglutarate-with-progressive-leukoencephalopathy-and-neurodegeneration
#8
Shenghong Ma, Renqiang Sun, Bowen Jiang, Jun Gao, Wanglong Deng, Peng Liu, Ruoyu He, Jing Cui, Minbiao Ji, Wei Yi, Pengyuan Yang, Xiaohui Wu, Yue Xiong, Zilong Qiu, Dan Ye, Kun-Liang Guan
L-2-hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of 2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs)...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28132785/allosteric-mutant-idh1-inhibitors-reveal-mechanisms-for-idh1-mutant-and-isoform-selectivity
#9
Xiaoling Xie, Daniel Baird, Kimberly Bowen, Vladimir Capka, Jinyun Chen, Gregg Chenail, YoungShin Cho, Julia Dooley, Ali Farsidjani, Pascal Fortin, Darcy Kohls, Raviraj Kulathila, Fallon Lin, Daniel McKay, Lindsey Rodrigues, David Sage, Simon van der Plas, Kirk Wright, Ming Xu, Hong Yin, Julian Levell, Raymond A Pagliarini
Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1(R132H) mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity...
January 18, 2017: Structure
https://www.readbyqxmd.com/read/28124097/pan-mutant-idh1-inhibitor-bay-1436032-for-effective-treatment-of-idh1-mutant-astrocytoma-in-vivo
#10
Stefan Pusch, Sonja Krausert, Viktoria Fischer, Jörg Balss, Martina Ott, Daniel Schrimpf, David Capper, Felix Sahm, Jessica Eisel, Ann-Christin Beck, Manfred Jugold, Viktoria Eichwald, Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp, Markus Bauser, Wolfgang Wick, Andreas Unterberg, Christel Herold-Mende, Michael Platten, Andreas von Deimling
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations...
January 25, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28115720/drosophila-larvae-synthesize-the-putative-oncometabolite-l-2-hydroxyglutarate-during-normal-developmental-growth
#11
Hongde Li, Geetanjali Chawla, Alexander J Hurlburt, Maria C Sterrett, Olga Zaslaver, James Cox, Jonathan A Karty, Adam P Rosebrock, Amy A Caudy, Jason M Tennessen
L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncometabolite that is capable of inhibiting enzymes involved in metabolism, chromatin modification, and cell differentiation. However, despite the ability of L-2HG to interfere with a broad range of cellular processes, this molecule is often characterized as a metabolic waste product. Here, we demonstrate that Drosophila larvae use the metabolic conditions established by aerobic glycolysis to both synthesize and accumulate high concentrations of L-2HG during normal developmental growth...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
Lin 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...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27847299/an-mrspec-database-query-and-visualization-engine-with-applications-as-a-clinical-diagnostic-and-research-tool
#20
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
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