Interestingly, in all studies the frequency of IDH mutations was higher in A II than in AA III. L-2-hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Elevated D2HG inhibits appropriate hydroxylation of collagen, leading to alterations in the ECM. Isocitrate dehydrogenase (IDH) has three isoforms—two in the mitochondrion, an NADP+-linked IDH2 and an NAD+-linked IDH3, and one in the cytosol, an NADP+-linked form. 7). The same IDH mutations have also been observed in myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), both of which are precursor conditions that can progress to AML (33). Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. In vitro analyses of these lines have shown that cell membranes are not permeable to D2HG and that this metabolite is not readily taken up by cells in culture, compromising the direct investigation of the effects of IDH mutations and D2HG in controlled experimental systems (50). This chiral molecule is very similar in structure to the achiral 2-OG and is normally present at low levels in both its D- (or R-) and L- (or S-) enantiomeric forms. N.V. Bhagavan, Chung-Eun Ha, in Essentials of Medical Biochemistry (Second Edition), 2015. by adding a phosphate to the protein chain, which blocks the reaction. capturing the energy of disassembly at each step. decides which reaction is appropriate based on the level of AMP in the cell: when levels The DNA-demethylating agents 5-azacytidine (5-Aza-CR) and 5-aza-2′-deoxycytidine (5-Aza-CdR, decitabine) act as DNA methyltransferase inhibitors and are already used in treating patients with high-risk MDS and AML (75). The first structures studied the complex of the enzyme with each of its Structures are available for most of the enzymes in the citric acid cycle. Although 2-HG is easily monitored in the serum of AML patients, its presence may be less specific in glioma (Capper et al., 2012). There is a significant association of IDH mutations with mutations in nucleophosmin mutations in patients with AML with a normal cytogenetic profile, placing them within a group of patients with an intermediate risk profile. Low NADPH levels may render glioma cells more sensitive to oxidative stress (Reitman and Yan, 2010). On the basis of molecular marker expression and microarray expression profiling, AITL is thought to arise from the follicular T-helper (TFH) cells that are present in germinal centers and cooperate with B cells in mounting an effective immune response (35, 36). It Be sure to use the biological unit when Characterization of these model tumors should soon yield fresh insights into IDH2-mutant AITL. The currently available evidence suggests that the ability of mutant IDH enzymes to promote tumorigenesis is due to their neomorphic enzyme activity and D2HG production. Therefore, mutation of an IDH enzyme could alter either the forward reaction or the reverse reaction or both, as well as upset the NADP/NADPH ratio. The explanation for these different findings and the molecular mechanism by which D2HG activates PHDs are yet to be determined. kinase/phosphatase. Further development of more specific epigenetic-modulating agents that can serve as useful tools in the management of IDH-mutant diseases is underway. In both cases, the progeny were born at the expected Mendelian ratio and displayed no gross phenotype early in life. 2-HG can impair function of α-KG-dependent proteins, affecting a wide range of cellular functions including DNA demethylation, histone demethylation, fatty acid metabolism, hypoxic state detection, and collagen modification among others (Loenarz & Schofield, 2008). Histone methylation at some key H3 lysine residues was also increased, consistent with D2HG-mediated inhibition of histone demethylases. IDH1 is predominantly cytoplasmic, while IDH2 can be found in the cell mitochondria. mechanism of NADP+-dependent isocitrate dehydrogenase: implications from the Learning about their diverse shapes and functions helps to understand all aspects of biomedicine and agriculture, from protein synthesis to health and disease to biological energy. chance to react. A global DNA hypermethylated state is observed in mutant IDH1 gliomas, as well as IDH1/2 mutant AML samples (Figueroa et al., 2010; Noushmehr et al., 2010). are high, AMP binds to a regulatory site, activating the phosphate-removing machinery, otherwise it is Figure 12.12. structures of magnesium-isocitrate and NADP+ complexes. In mammalian cells, the heart and skeletal muscle contain predominantly the mitochondrial NADP-specific enzyme (McFarlane et al., 1977). In all cases, the mutations in IDH1 and IDH2 were mutually exclusive and present in the hemizygous state. Bhardwaj, in Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease, 2013. cells. Given the positioning of IDH1 and IDH2 in the cellular metabolic network, and their ability to produce NADPH, mutations in these enzymes may perturb cellular metabolism in profound ways that contribute to tumorigenesis. (8icd ), IDH proteins have emerged as important new targets in glioma, particularly in grade II/III gliomas and in secondary GBM. Bacteria take a simpler approach. In contrast, HIF1 levels and HIF1 target genes were not altered in hematopoietic cells in the LysM-Cre IDH1R132H or Vav-Cre IDH1R132H mice discussed above, suggesting that effects on HIF signaling may be context dependent (4). Background: Isocitrate dehydrogenase (IDH) mutant is one of the most robust and important genetic aberrations in glioma. Note that in comparison with the glycolytic pathway, none of the CAC intermediates are phosphorylated. Using a metabolite profiling strategy, they discovered that the mutant IDH enzymes acquire a neomorphic activity in which the normal product α-KG is converted to 2-hydroxyglutarate (2-HG) in a reaction that consumes, rather than produces, NADPH (ref. It may also soon be possible to develop therapeutic strategies that specifically target IDH-mutant disease. (1idc ). of the intermediate oxalosuccinate before it loses the carbon dioxide This should be no surprise, though, since glucose is the central fuel used by oxygen-breathing organisms. At the time, this discovery represented a major success for cancer genome sequencing projects and sparked a flurry of investigations aimed at understanding the role that IDH mutations play in tumorigenesis. This observation supports the hypothesis that the gain-of-function of the mutant enzyme and its production of D2HG are critical for the tumor-promoting effects of mutated IDH1. NADP The D2HG molecule itself can also be directly imaged using nuclear magnetic resonance spectroscopy, allowing for noninvasive mapping of D2HG accumulation in an affected tissue (69, 70). Citrate synthetase. In vitro biochemical studies have shown that both D2HG and L2HG can act as competitive inhibitors of 2-OG–dependent dioxygenases by binding to the α-KG–binding pocket in the enzyme's active site (42). Hence, D2HG has been described as an “oncometabolite” in glioma and AML. Reactions are shown for four classes of 2-OG–dependent dioxygenases potentially inhibited by D2HG. The collagen PHD and LHD hydroxylate proline and lysine residues of collagen during its maturation in the endoplasmic reticulum. D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats, Enzyme redesign guided by cancer-derived IDH1 mutations, IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors, Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers, IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours, Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome, Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2, Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas, Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping, IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma, Molecular pathogenesis of IDH mutations in gliomas, Analysis of the IDH1 codon 132 mutation in brain tumors, Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology, All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2, IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas, The role of mutations in epigenetic regulators in myeloid malignancies, Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation, Pathobiology and molecular profiling of peripheral T-cell lymphomas, Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma, Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with T-FH-like features and adverse clinical parameters, Angioimmunoblastic T-cell lymphoma mice model, IDH mutations: new genetic signatures in cholangiocarcinoma and therapeutic implications, Immunohistochemical demonstration of isocitrate dehydrogenase 1 (IDH1) mutation in a small subset of prostatic carcinomas, Inhibition of 2-oxoglutarate dependent oxygenases, The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases, TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis, Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies, Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma, TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations, Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas, IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype, A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation, Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases, IDH mutation impairs histone demethylation and results in a block to cell differentiation, Collagens, modifying enzymes and their mutations in humans, flies and worms, FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia, Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates, HIF-independent role of prolyl hydroxylases in the cellular response to amino acids, Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation, (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible, Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia, Reductive carboxylation supports growth in tumour cells with defective mitochondria, Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability, Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome, Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone, Mutant IDH1 is required for IDH1 mutated tumor cell growth, D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function, IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics, Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex, Monoclonal antibody specific for IDH1 R132H mutation, 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas, Magnetic resonance of 2-hydroxyglutarate in IDH1-mutated low-grade gliomas, Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response, Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG, An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells, Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation, Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy, Cancer Epidemiology, Biomarkers & Prevention, Disclosure of Potential Conflicts of Interest.

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