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2 hydroxyglutarate

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https://www.readbyqxmd.com/read/28404805/mutant-idh1-and-seizures-in-patients-with-glioma
#1
Hao Chen, Jonathon Judkins, Cheddhi Thomas, Meijing Wu, Laith Khoury, Carolina G Benjamin, Donato Pacione, John G Golfinos, Priya Kumthekar, Farhad Ghamsari, Li Chen, Pamela Lein, Dane M Chetkovich, Matija Snuderl, Craig Horbinski
OBJECTIVE: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1(mut)) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1(mut) increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. METHODS: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1(mut) status...
April 12, 2017: Neurology
https://www.readbyqxmd.com/read/28402860/idh1-mutation-promotes-tumorigenesis-by-inhibiting-jnk-activation-and-apoptosis-induced-by-serum-starvation
#2
Bin Jiang, Jia Zhang, Jinmei Xia, Wentao Zhao, Yanan Wu, Minggang Shi, Lianzhong Luo, Huamin Zhou, Ai Chen, Huanhuan Ma, Qingwen Zhao, Muhammad Suleman, Furong Lin, Lin Zhou, Jinyang Wang, Yan Zhang, Ying He, Xiaotong Li, Li-Man Hung, Tak Wah Mak, Qinxi Li
Two hallmarks of cancer cells are their resistance to apoptosis and ability to thrive despite reduced levels of vital serum components. c-jun N-terminal kinase (JNK) activation is crucial for apoptosis triggered by serum starvation (SS), and isocitrate dehydrogenase 1 (IDH1) mutations are tumorigenic, in part, because they produce the abnormal metabolite 2-hydroxyglutarate (2-HG). However, it is unknown whether 2-HG-induced tumorigenesis is partially due to JNK inhibition and thus defective SS-induced apoptosis...
April 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28396261/experimental-evidence-of-oxidative-stress-in-patients-with-l-2-hydroxyglutaric-aciduria-and-that-l-carnitine-attenuates-in-vitro-dna-damage-caused-by-d-2-hydroxyglutaric-and-l-2-hydroxyglutaric-acids
#3
Daiane Grigolo Bardemaker Rodrigues, Daniella de Moura Coelho, Ângela Sitta, Carlos Eduardo Diaz Jacques, Tatiane Hauschild, Vanusa Manfredini, Abdellatif Bakkali, Eduard A Struys, Cornelis Jakobs, Moacir Wajner, Carmen Regla Vargas
d-2-hydroxyglutaric (D-2-HGA) and l-2-hydroxyglutaric (L-2-HGA) acidurias are rare neurometabolic disorders biochemically characterized by increased levels of d-2-hydroxyglutaric acid (D-2-HG) and l-2-hydroxyglutaric acid (L-2-HG) respectively, in biological fluids and tissues. These diseases are caused by mutations in the specific enzymes involved in the metabolic pathways of these organic acids. In the present work, we first investigated whether D-2-HG and L-2-HGA could provoke DNA oxidative damage in blood leukocytes and whether l-carnitine (LC) could prevent the in vitro DNA damage induced by these organic acids...
April 7, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28375741/isocitrate-dehydrogenase-mutation-and-r-2-hydroxyglutarate-from-basic-discovery-to-therapeutics-development
#4
Lenny Dang, Shin-San Michael Su
The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms nicotinamide adenine dinucleotide phosphate-dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide-dependent IDH3) contribute to regulating the circuitry of central metabolism...
April 3, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28358347/the-enzymology-of-2-hydroxyglutarate-2-hydroxyglutaramate-and-2-hydroxysuccinamate-and-their-relationship-to-oncometabolites
#5
Vivek A Hariharan, Travis T Denton, Sarah Paraszcszak, Kyle McEvoy, Thomas M Jeitner, Boris F Krasnikov, Arthur J L Cooper
Many enzymes make "mistakes". Consequently, repair enzymes have evolved to correct these mistakes. For example, lactate dehydrogenase (LDH) and mitochondrial malate dehydrogenase (mMDH) slowly catalyze the reduction of 2-oxoglutarate (2-OG) to the oncometabolite l-2-hydroxyglutarate (l-2-HG). l-2-HG dehydrogenase corrects this error by converting l-2-HG to 2-OG. LDH also catalyzes the reduction of the oxo group of 2-oxoglutaramate (2-OGM; transamination product of l-glutamine). We show here that human glutamine synthetase (GS) catalyzes the amidation of the terminal carboxyl of both the l- and d- isomers of 2-HG...
March 30, 2017: Biology
https://www.readbyqxmd.com/read/28346139/oncometabolite-d-2-hydroxyglutarate-enhances-gene-silencing-through-inhibition-of-specific-h3k36-histone-demethylases
#6
Ryan Janke, Anthony T Iavarone, Jasper Rine
Certain mutations affecting central metabolism cause accumulation of the oncometabolite D-2-hydroxyglutarate which promotes progression of certain tumors. High levels of D-2-hydroxyglutarate inhibit the TET family of DNA demethylases and Jumonji family of histone demethylases and cause epigenetic changes that lead to altered gene expression. The link between inhibition of DNA demethylation and changes in expression is strong in some cancers, but not in others. To determine whether D-2-hydroxyglutarate can affect gene expression through inhibiting histone demethylases, orthologous mutations to those known to cause accumulation of D-2-hydroxyglutarate in tumors were generated in Saccharomyces cerevisiae, which has histone demethylases but not DNA methylases or demethylases...
March 27, 2017: ELife
https://www.readbyqxmd.com/read/28330869/molecular-mechanisms-of-isocitrate-dehydrogenase-1-idh1-mutations-identified-in-tumors-the-role-of-size-and-hydrophobicity-at-residue-132-on-catalytic-efficiency
#7
Diego Avellaneda Matteo, Adam J Grunseth, Eric R Gonzalez, Stacy L Anselmo, Madison A Kennedy, Precious Moman, David A Scott, An Hoang, Christal D Sohl
Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP+-dependent conversion of isocitrate (ICT) to α-ketoglutarate (αKG) in the cytosol and peroxisomes. Mutations in IDH1 have been implicated in > 80% of lower grade gliomas and secondary glioblastomas and primarily affect residue 132, which helps coordinate substrate binding. However, other mutations found in the active site have also been identified in tumors. IDH1 mutations typically result in a loss of catalytic activity, but many also can catalyze a new reaction, the NADPH-dependent reduction of αKG to D-2-hydroxyglutarate (D2HG)...
March 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28327577/metabolic-profiling-of-idh-mutation-and-malignant-progression-in-infiltrating-glioma
#8
Llewellyn E Jalbert, Adam Elkhaled, Joanna J Phillips, Evan Neill, Aurelia Williams, Jason C Crane, Marram P Olson, Annette M Molinaro, Mitchel S Berger, John Kurhanewicz, Sabrina M Ronen, Susan M Chang, Sarah J Nelson
Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM)...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28319049/resisting-fatal-attraction-a-glioma-oncometabolite-prevents-cd8-t-cell-recruitment
#9
Liliana E Lucca, David A Hafler
Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28319047/isocitrate-dehydrogenase-mutations-suppress-stat1-and-cd8-t-cell-accumulation-in-gliomas
#10
Gary Kohanbash, Diego A Carrera, Shruti Shrivastav, Brian J Ahn, Naznin Jahan, Tali Mazor, Zinal S Chheda, Kira M Downey, Payal B Watchmaker, Casey Beppler, Rolf Warta, Nduka A Amankulor, Christel Herold-Mende, Joseph F Costello, Hideho Okada
Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte-associated genes and IFN-γ-inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28315358/isocitrate-dehydrogenase-idh-inhibition-as-treatment-of-myeloid-malignancies-progress-and-future-directions
#11
REVIEW
Vivek A Upadhyay, Andrew M Brunner, Amir T Fathi
Isocitrate dehydrogenase (IDH) is an essential metabolic enzyme. Over the last two decades, there has been a growing focus on the metabolic derangements that occur with IDH1 and IDH2 mutations. The altered IDH protein leads to accumulation of 2-hydroxyglutarate (2-HG), a metabolite with oncogenic activity via epigenetic mechanisms. The advent of IDH inhibitors has engendered hope in novel and targeted therapies in IDH1/2 mutant myeloid malignancies. We here summarize the basic physiology of IDH, the metabolic and oncogenic consequences of mutant IDH1/2, and the clinical significance of IDH inhibition in hematologic malignancies...
March 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28298040/noninvasive-assessment-of-isocitrate-dehydrogenase-mutation-status-in-cerebral-gliomas-by-magnetic-resonance-spectroscopy-in-a-clinical-setting
#12
Anna Tietze, Changho Choi, Bruce Mickey, Elizabeth A Maher, Benedicte Parm Ulhøi, Ryan Sangill, Yasmin Lassen-Ramshad, Slavka Lukacova, Leif Østergaard, Gorm von Oettingen
OBJECTIVE Mutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme. METHODS By extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol...
March 3, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28273642/idh-mutations-associated-impact-on-related-cancer-epidemiology-and-subsequent-effect-toward-hif-1%C3%AE
#13
REVIEW
Herve Semukunzi, Debmalya Roy, Hongyang Li, Ghulam Jilany Khan, Xiaodan Lyu, Shengtao Yuan, Sensen Lin
Particular mutations in the isocitrate dehydrogenase gene (IDH) were discovered in several gliomas citing astrocytoma, oligodendroglioma, and glioblastoma multiform, but also in leukemia; these mutations were discovered in nearly all cases of secondary glioblastomas, they evolve from lower-grade gliomas, but are limited in primary high-grade glioblastoma multiform. These mutations distinctively produce (D)-2-hydroxyglutarate (D-2-HG) from alpha-ketoglutarate (α-KG). (D)-2-hydroxyglutarate is accumulated to very high concentrations which inhibit the function of enzymes that are dependent on alpha-ketoglutarate...
March 5, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28269980/oncometabolites-d-and-l-2-hydroxyglutarate-inhibit-the-alkb-family-dna-repair-enzymes-under-physiological-conditions
#14
Fangyi Chen, Ke Bian, Qi Tang, Bogdan I Fedeles, Vipender Singh, Zachary T Humulock, John M Essigmann, Deyu Li
Cancer-associated mutations often lead to perturbed cellular energy metabolism and accumulation of potentially harmful oncometabolites. One example is the chiral molecule 2-hydroxyglutarate (2HG); its two stereoisomers (d- and l-2HG) have been found at abnormally high concentrations in tumors featuring anomalous metabolic pathways. 2HG has been demonstrated to competitively inhibit several α-ketoglutarate (αKG)- and non-heme iron-dependent dioxygenases, including some of the AlkB family DNA repair enzymes, such as ALKBH2 and ALKBH3...
April 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28263965/l-2-hydroxyglutarate-production-arises-from-noncanonical-enzyme-function-at-acidic-ph
#15
Andrew M Intlekofer, Bo Wang, Hui Liu, Hardik Shah, Carlos Carmona-Fontaine, Ariën S Rustenburg, Salah Salah, M R Gunner, John D Chodera, Justin R Cross, Craig B Thompson
The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via 'promiscuous' reduction of the alternative substrate αKG...
May 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28248126/prospective-longitudinal-analysis-of-2-hydroxyglutarate-magnetic-resonance-spectroscopy-identifies-broad-clinical-utility-for-the-management-of-patients-with-idh-mutant-glioma
#16
Changho Choi, Jack M Raisanen, Sandeep K Ganji, Song Zhang, Sarah S McNeil, Zhongxu An, Akshay Madan, Kimmo J Hatanpaa, Vamsidhara Vemireddy, Christie A Sheppard, Dwight Oliver, Keith M Hulsey, Vivek Tiwari, Tomoyuki Mashimo, James Battiste, Samuel Barnett, Christopher J Madden, Toral R Patel, Edward Pan, Craig R Malloy, Bruce E Mickey, Robert M Bachoo, Elizabeth A Maher
Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment...
November 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28219702/genetic-alterations-in-krebs-cycle-and-its-impact-on-cancer-pathogenesis
#17
REVIEW
Karishma Sajnani, Farhadul Islam, Robert Anthony Smith, Vinod Gopalan, Alfred King-Yin Lam
Cancer cells exhibit alterations in many cellular processes, including oxygen sensing and energy metabolism. Glycolysis in non-oxygen condition is the main energy production process in cancer rather than mitochondrial respiration as in benign cells. Genetic and epigenetic alterations of Krebs cycle enzymes favour the shift of cancer cells from oxidative phosphorylation to anaerobic glycolysis. Mutations in genes encoding aconitase, isocitrate dehydrogenase, succinate dehydrogenase, fumarate hydratase, and citrate synthase are noted in many cancers...
April 2017: Biochimie
https://www.readbyqxmd.com/read/28193778/ag-221-a-first-in-class-therapy-targeting-acute-myeloid-leukemia-harboring-oncogenic-idh2-mutations
#18
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
#19
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
#20
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...
April 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
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