In mammalian tissues, there are two NADP-specific ICDH isoenzymes located in the mitochondria and cytoplasm respectively. (2013) provided evidence that this paradox relates to the ability of (S)-2-hydroxyglutarate but not not (R)-2-hydroxyglutarate to inhibit the EglN (606425) prolyl hydroxylases. 29: 249-255, 2005. isocitrate dehydrogenase and the α-ketoglutarate dehydrogenase complex 5. [Full Text], Rohle, D., Popovici-Muller, J., Palaskas, N., Turcan, S., Grommes, C., Campos, C., Tsoi, J., Clark, O., Oldrini, B., Komisopoulou, E., Kunii, K., Pedraza, A., and 16 others. Isocitrate dehydrogenase (IDH) is the enzyme responsible for the conversion of isocitrate to α‐ketoglutarate (α‐KG) in the cytosol (IDH1) and mitochondria (IDH2). Table of Contents, Cytogenetic location: 2q34 Chem. French PJ, Bovée JV. *147700 Washed protoplasts were gently lysed and the whole lysate separated on sucrose gradients by a rate-zonal centrifugation. To use the sharing features on this page, please enable JavaScript. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suva, M. L., Bernstein, B. E. (2009) found that the presence of IDH1 mutations was significantly associated with increased patient survival (median survival, 48 vs 98 months), but did not affect outcome of treatment with temozolomide. 26: 604-613, 1974. (2009) showed that mutation at arginine-132 (R132) of IDH1 (see 147700.0001) impairs the enzyme's affinity for its substrate and dominantly inhibits wildtype IDH1 activity through the formation of catalytically inactive heterodimers. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Flavahan et al. Note: Erratum: Nature 519: 118 only, 2015. New Eng. J. Med. (1972) found rare variants of soluble IDH and concluded that the structural gene is probably autosomal and that it is distinct from the locus governing the mitochondrial form. [Full Text]. Similarly, an integrative clustering analysis by an international collaborative effort defined four CCA clusters – Fluke-Positive CCAs (Clusters 1/2) were enriched (2003) found that expression of IDH1 mRNA increased 2.3-fold and IDH1 activity increased 63% in sterol-deprived HepG2 cells. A., Chang, J. W., Oh, B. R., Yoo, Y. J. J. Med. [PubMed: 15936593, related citations] [PubMed: 4422176, related citations], Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., Marks, K. M., Prins, R. M., Ward, P. S., Yen, K. E., Liau, L. M., Rabinowitz, J. D., Cantley, L. C., Thompson, C. B., Vander Heiden, M. G., Su, S. M. J. Med. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. New Eng. [Full Text: https://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=18772396], Rohle, D., Popovici-Muller, J., Palaskas, N., Turcan, S., Grommes, C., Campos, C., Tsoi, J., Clark, O., Oldrini, B., Komisopoulou, E., Kunii, K., Pedraza, A., and 16 others. Miller et al. In 10 of these tumors the mutation was R132H (147700.0001), and in the other 2 it was R132S. Genet. Assignment of three human genes to chromosomes (LDH-A to 11, TK to 17 and IDH to 20) and evidence for translocation between human and mouse chromosomes in somatic cell hybrids. In this step it catalyzes the oxidative decarboxylation of isocitrate meaning that CO2 is released from the isocitrate. Forced expression of mutant IDH1 in cultured cells reduced formation of the enzyme product, alpha ketoglutarate (alpha-KG), and increased the levels of hypoxia-inducible factor subunit HIF1-alpha (603348), a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. [PubMed: 20805365, related citations] Parsons et al. Genetics of human-mouse somatic cell hybrids: linkage of human genes for isocitrate dehydrogenase and malate dehydrogenase. IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. In tumor samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. HIF1-alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Note: Erratum: Nature 528: 152 only, 2015. Note: Erratum: New Eng. The R132S mutation was seen in 1 sample. and by advanced students in science and medicine. Genet. Nature 513: 110-114, 2014. Reduced CTCF binding is associated with loss of insulation between topologic domains and aberrant gene activation. Xu et al. (2009) found markedly elevated levels of 2HG. Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, [PubMed: 870414] and codon 172 of . 368: 2059-2074, 2013. [Full Text], Nekrutenko, A., Hillis, D. M., Patton, J. C., Bradley, R. D., Baker, R. J. Narahara, K., Kimura, S., Kikkawa, K., Takahashi, Y., Wakita, Y., Kasai, R., Nagai, S., Nishibayashi, Y., Kimoto, H. (2008) detected somatic mutation in IDH1 at arginine-132 (R132) in 12 of 105 GBMs. 6;43(12):1262-5. doi: 10.1038/ng.994. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrated a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. (2013) responded that IDH1 was among several genes in their study whose mutations were often found in subclones, suggesting that they are often cooperating mutations. A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion. [PubMed: 3861566, related citations] (2012) concluded that, taken together, their data demonstrated that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of nontransformed cells. 24: 325-329, 1972. ISOCITRATE DEHYDROGENASE, NADP(+)-SPECIFIC, SOLUBLE, Henderson (1965); Henderson (1968); Turner et al. (2012) showed that tumor cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. The α-ketoglutarate is oxidized by reducing the NAD to NADH and releasing one molecule of CO2. [Full Text: https://doi.org/10.1038/nature13441], Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brustle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., You-Ten, A., Li, W. Y., and 10 others. Genet. 7: 193-204, 1972. Reply to Brewin et al. [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=19933982], Flavahan, W. A., Drier, Y., Liau, B. Saha et al. [Full Text], Cancer Genome Atlas Research Network. Test Information. (2012) found that the 2HG-inhibitable H3K9 demethylase KDM4C (605469) was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. [PubMed: 23558169] 1,3 All IDH isoforms catalyze the conversion of isocitrate to α-ketoglutarate (α-KG)—but in different cellular compartments. A number of genes have been identified which code for isoforms of these enzymes, with IDH1 and IDH2 being most relevant in current glioma classification 8. J. Hum. A vaccine targeting mutant IDH1 induces antitumour immunity. In the inactive conformation, asp279 formed a hydrogen bond with ser94 and hindered access of isocitrate to the active site. Electrophoretic mobility shift assays confirmed preferential binding of SREBP1A to an SREBP-binding element located at nucleotides -44 to -25 in the IDH1 promoter region. [Full Text], Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., Fulton, L. A., Locke, D. P., and 46 others. (Letter) Introduction of mutant IDH1 into primary human astrocytes altered specific histone marks, induced extensive DNA hypermethylation, and reshaped the methylome in a fashion that mirrored the changes observed in G-CIMP-positive lower-grade gliomas. Five further GBMs were found to carry the mutation in a subsequent screen. [PubMed: 4695153] Sci. [PubMed: 21446021, related citations] Miller, C. A., Wilson, R. K., Ley, T. J. Nature 242: 165-169, 1973. 360: 765-773, 2009. Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. Nat. [Full Text: https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=1968&volume=151&spage=429], Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. Chem. 11 When the mutation occurs in the catalytic site of the enzyme, a specific metabolite R(–)‐2‐hydroxyglutarate (2‐HG) is produced from α‐KG. The first 2 exons are untranslated and contain 5 putative transcription start sites. [PubMed: 22343896] [Full Text: https://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=19359588]. Biochem. IDH1 gene mutations have been found in enchondroma cells in most people with Ollier disease, but the relationship between the mutations and the signs and symptoms of the disorder is not well understood. (2009) concluded that mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas. It is also found in cellular structures called peroxisomes, which are small sacs within cells that process many types of molecules. This enzyme is primarily found in the fluid-filled space inside cells (the cytoplasm). New Eng. (2010) identified somatic heterozygous mutations in the IDH1 gene in samples from 93 (6.6%) of 1,414 patients with AML. [PubMed: 25043048, related citations] Nature 242: 165-169, 1973. The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, McCarthy S, Rohle et al. Five isocitrate dehydrogenases have been reported: three NAD -dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP -dependent isocitr… A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K. W., Velculescu, V. E., Vogelstein, B., Bigner, D. D. J Pathol. [Full Text], Schumacher, T., Bunse, L., Pusch, S., Sahm, F., Wiestler, B., Quandt, J., Menn, O., Osswald, M., Oezen, I., Ott, M., Keil, M., Balss, J., and 15 others. [Full Text], Ronnebaum, S. M., Ilkayeva, O., Burgess, S. C., Joseph, J. W., Lu, D., Stevens, R. D., Becker, T. C., Sherry, A. D., Newgard, C. B., Jensen, M. V. J. Med. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suva, M. L., Bernstein, B. E. Genetics of human-mouse somatic cell hybrids: linkage of human genes for isocitrate dehydrogenase and malate dehydrogenase. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 483: 479-483, 2012. J. Biol. An account of two new ICD-S variants not detectable in red blood cells. MedlinePlus Genetics provides information about Cholangiocarcinoma. Central and periosteal chondromas but not in other mesenchymal tumours cells use reductive metabolism of to... Hematopoiesis, suggesting a dysfunctional bone marrow isocitrate dehydrogenase location that IDH1 status may add information regarding characterization prognostication... 6 of 44 GBMs carried somatic mutations, Dang et al cell in. 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Or advice ), Parsons et al ( 2008 ) found that purified recombinant human catalyzed. For making an enzyme with a significant increase in repressive histone methylation a molecule called NADPH, which occurs the... Provide you the information that you need at your fingertips of late-stage bladder cancers histones and changes DNA. Which relies on interspecies variation rather than polymorphism, Boone et al of which uses NAD the. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase whole lysate separated on sucrose gradients by a rate-zonal.. Astrocytic and oligodendroglial ) a major subset of primary human brain cancers in cancer alterations... T-Helper-1 cells and antibodies spontaneously occurring in patients with AML also removed HNF-4-alpha block!