PDBsum entry 3inm

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
Protein chain
407 a.a. *
NDP ×3
AKG ×3
GOL ×3
_NA ×3
_CA ×3
Waters ×301
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure of human cytosolic NADP(+)-dependent isoci dehydrogenase r132h mutant in complex with NADPH, alpha-ket and calcium(2+)
Structure: Isocitrate dehydrogenase [nadp] cytoplasmic. Chain: a, b, c. Synonym: idh, cytosolic NADP-isocitrate dehydrogenase, oxal decarboxylase, NADP(+)-specific icdh, idp. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: idh1, picd. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.10Å     R-factor:   0.222     R-free:   0.262
Authors: E.Fontano,R.S.Brown,R.K.Suto,B.Bhyravbhatla
Key ref:
L.Dang et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 462, 739-744. PubMed id: 19935646 DOI: 10.1038/nature08617
12-Aug-09     Release date:   24-Nov-09    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
O75874  (IDHC_HUMAN) -  Isocitrate dehydrogenase [NADP] cytoplasmic
414 a.a.
407 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Isocitrate dehydrogenase (NADP(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Citric acid cycle
      Reaction: Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH
Bound ligand (Het Group name = NDP)
corresponds exactly
Bound ligand (Het Group name = AKG)
corresponds exactly
+ CO(2)
      Cofactor: Mn(2+) or Mg(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   6 terms 
  Biological process     small molecule metabolic process   13 terms 
  Biochemical function     oxidoreductase activity     9 terms  


DOI no: 10.1038/nature08617 Nature 462:739-744 (2009)
PubMed id: 19935646  
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
L.Dang, D.W.White, S.Gross, B.D.Bennett, M.A.Bittinger, E.M.Driggers, V.R.Fantin, H.G.Jang, S.Jin, M.C.Keenan, K.M.Marks, R.M.Prins, P.S.Ward, K.E.Yen, L.M.Liau, J.D.Rabinowitz, L.C.Cantley, C.B.Thompson, M.G.Vander Heiden, S.M.Su.
Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
  Selected figure(s)  
Figure 3.
Figure 3: Structural analysis of R132H mutant IDH1. a, On the left is shown an overlay of R132H mutant IDH1 (green) and wild-type IDH1 (grey) structures in the ‘closed’ conformation. On the right is shown an overlay of wild-type IDH1 (blue) structure in the ‘open’ conformation with mutant IDH1 (green) for comparison. b, Close-up comparison of the R132H IDH1 active site (left) with α-ketoglutarate (yellow) and NADPH (grey) and the wild-type IDH1 active site (right) with isocitrate (yellow) and NADP (grey). Residues coming from the other monomer are denoted with a prime (′) symbol. In addition to the mutation at residue 132, the major changes are the positions of the catalytic residues Tyr 139 and Lys 212′. c, Wall-eyed stereo image showing the composite omit map for α-ketoglutarate, NADPH, calcium ion, His 132 and other key catalytic residues in the R132H mutant active site contoured at the 1σ level.
Figure 4.
Figure 4: Human malignant gliomas containing R132 mutations in IDH1 contain increased concentrations of 2HG. Human glioma samples obtained by surgical resection were snap frozen, genotyped to stratify as wild type (n = 10) or carrying an R132 mutant allele (mutant) (n = 12) and metabolites extracted for LC–MS analysis. Among the 12 mutant tumours, 10 carried a R132H mutation, one an R132S mutation, and one an R132G mutation. Each symbol represents the amount of the listed metabolite found in each tumour sample. Horizontal lines indicate the group sample means. The difference in 2HG observed between wild-type and R132 mutant IDH1 tumours was statistically significant by Student’s t-test (P < 0.0001). There were no statistically significant differences in α-ketoglutarate, malate, fumarate, succinate, or isocitrate levels between the wild-type and R132 mutant IDH1 tumours.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2009, 462, 739-744) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22898539 A.H.Shih, O.Abdel-Wahab, J.P.Patel, and R.L.Levine (2012).
The role of mutations in epigenetic regulators in myeloid malignancies.
  Nat Rev Cancer, 12, 599-612.  
23151579 A.Schulze, and A.L.Harris (2012).
How cancer metabolism is tuned for proliferation and vulnerable to disruption.
  Nature, 491, 364-373.  
22343901 C.Lu, P.S.Ward, G.S.Kapoor, D.Rohle, S.Turcan, O.Abdel-Wahab, C.R.Edwards, R.Khanin, M.E.Figueroa, A.Melnick, K.E.Wellen, D.M.O'Rourke, S.L.Berger, T.A.Chan, R.L.Levine, I.K.Mellinghoff, and C.B.Thompson (2012).
IDH mutation impairs histone demethylation and results in a block to cell differentiation.
  Nature, 483, 474-478.  
23001348 D.C.Wallace (2012).
Mitochondria and cancer.
  Nat Rev Cancer, 12, 685-698.  
22436749 G.J.Patti, O.Yanes, and G.Siuzdak (2012).
Innovation: Metabolomics: the apogee of the omics trilogy.
  Nat Rev Mol Cell Biol, 13, 263-269.  
22286061 J.Schwartzentruber, A.Korshunov, X.Y.Liu, D.T.Jones, E.Pfaff, K.Jacob, D.Sturm, A.M.Fontebasso, D.A.Quang, M.Tönjes, V.Hovestadt, S.Albrecht, M.Kool, A.Nantel, C.Konermann, A.Lindroth, N.Jäger, T.Rausch, M.Ryzhova, J.O.Korbel, T.Hielscher, P.Hauser, M.Garami, A.Klekner, L.Bognar, M.Ebinger, M.U.Schuhmann, W.Scheurlen, A.Pekrun, M.C.Frühwald, W.Roggendorf, C.Kramm, M.Dürken, J.Atkinson, P.Lepage, A.Montpetit, M.Zakrzewska, K.Zakrzewski, P.P.Liberski, Z.Dong, P.Siegel, A.E.Kulozik, M.Zapatka, A.Guha, D.Malkin, J.Felsberg, G.Reifenberger, A.von Deimling, K.Ichimura, V.P.Collins, H.Witt, T.Milde, O.Witt, C.Zhang, P.Castelo-Branco, P.Lichter, D.Faury, U.Tabori, C.Plass, J.Majewski, S.M.Pfister, and N.Jabado (2012).
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.
  Nature, 482, 226-231.  
23274470 M.N.Patel, M.D.Halling-Brown, J.E.Tym, P.Workman, and B.Al-Lazikani (2012).
Objective assessment of cancer genes for drug discovery.
  Nat Rev Drug Discov, 12, 35-50.  
22763442 M.Sasaki, C.B.Knobbe, J.C.Munger, E.F.Lind, D.Brenner, A.Brüstle, I.S.Harris, R.Holmes, A.Wakeham, J.Haight, A.You-Ten, W.Y.Li, S.Schalm, S.M.Su, C.Virtanen, G.Reifenberger, P.S.Ohashi, D.L.Barber, M.E.Figueroa, A.Melnick, J.C.Zúñiga-Pflücker, and T.W.Mak (2012).
IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics.
  Nature, 488, 656-659.  
22343896 P.Koivunen, S.Lee, C.G.Duncan, G.Lopez, G.Lu, S.Ramkissoon, J.A.Losman, P.Joensuu, U.Bergmann, S.Gross, J.Travins, S.Weiss, R.Looper, K.L.Ligon, R.G.Verhaak, H.Yan, and W.G.Kaelin (2012).
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.
  Nature, 483, 484-488.  
23222956 R.Piazza, S.Valletta, N.Winkelmann, S.Redaelli, R.Spinelli, A.Pirola, L.Antolini, L.Mologni, C.Donadoni, E.Papaemmanuil, S.Schnittger, D.W.Kim, J.Boultwood, F.Rossi, G.Gaipa, G.P.De Martini, P.F.di Celle, H.G.Jang, V.Fantin, G.R.Bignell, V.Magistroni, T.Haferlach, E.M.Pogliani, P.J.Campbell, A.J.Chase, W.J.Tapper, N.C.Cross, and C.Gambacorti-Passerini (2012).
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia.
  Nat Genet, 45, 18-24.  
22343889 S.Turcan, D.Rohle, A.Goenka, L.A.Walsh, F.Fang, E.Yilmaz, C.Campos, A.W.Fabius, C.Lu, P.S.Ward, C.B.Thompson, A.Kaufman, O.Guryanova, R.Levine, A.Heguy, A.Viale, L.G.Morris, J.T.Huse, I.K.Mellinghoff, and T.A.Chan (2012).
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype.
  Nature, 483, 479-483.  
21473982 A.Erez, O.A.Shchelochkov, S.E.Plon, F.Scaglia, and B.Lee (2011).
Insights into the pathogenesis and treatment of cancer from inborn errors of metabolism.
  Am J Hum Genet, 88, 402-421.  
21383721 A.Farrell (2011).
A close look at cancer.
  Nat Med, 17, 262-265.  
21415854 A.Schulze (2011).
A fresh look at cancer metabolism in a historical setting.
  EMBO Rep, 12, 289-291.  
21242296 A.Wolf, S.Agnihotri, J.Micallef, J.Mukherjee, N.Sabha, R.Cairns, C.Hawkins, and A.Guha (2011).
Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme.
  J Exp Med, 208, 313-326.  
21129061 A.von Deimling, A.Korshunov, and C.Hartmann (2011).
The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and IDH1 mutations.
  Brain Pathol, 21, 74-87.  
21163902 B.C.Christensen, A.A.Smith, S.Zheng, D.C.Koestler, E.A.Houseman, C.J.Marsit, J.L.Wiemels, H.H.Nelson, M.R.Karagas, M.R.Wrensch, K.T.Kelsey, and J.K.Wiencke (2011).
DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma.
  J Natl Cancer Inst, 103, 143-153.  
21301796 C.Frezza, P.J.Pollard, and E.Gottlieb (2011).
Inborn and acquired metabolic defects in cancer.
  J Mol Med, 89, 213-220.  
21301795 C.V.Dang, M.Hamaker, P.Sun, A.Le, and P.Gao (2011).
Therapeutic targeting of cancer cell metabolism.
  J Mol Med, 89, 205-212.  
21293295 D.A.Turner, and D.C.Adamson (2011).
Neuronal-astrocyte metabolic interactions: understanding the transition into abnormal astrocytoma metabolism.
  J Neuropathol Exp Neurol, 70, 167-176.  
21069360 D.Capper, D.Reuss, J.Schittenhelm, C.Hartmann, J.Bremer, F.Sahm, P.N.Harter, A.Jeibmann, and A.von Deimling (2011).
Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology.
  Acta Neuropathol, 121, 241-252.  
21225914 D.Rakheja, M.Mitui, R.L.Boriack, and R.J.DeBerardinis (2011).
Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors.
  Pediatr Blood Cancer, 56, 379-383.  
21080253 D.Rakheja, R.L.Boriack, M.Mitui, S.Khokhar, S.A.Holt, and P.Kapur (2011).
Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate.
  Tumour Biol, 32, 325-333.  
21054626 E.E.Bar (2011).
Glioblastoma, cancer stem cells and hypoxia.
  Brain Pathol, 21, 119-129.  
20816705 E.F.Mason, and J.C.Rathmell (2011).
Cell metabolism: an essential link between cell growth and apoptosis.
  Biochim Biophys Acta, 1813, 645-654.  
21554053 F.Ducray, A.Idbaih, X.W.Wang, C.Cheneau, M.Labussiere, and M.Sanson (2011).
Predictive and prognostic factors for gliomas.
  Expert Rev Anticancer Ther, 11, 781-789.  
21326614 G.Jin, Z.J.Reitman, I.Spasojevic, I.Batinic-Haberle, J.Yang, O.Schmidt-Kittler, D.D.Bigner, and H.Yan (2011).
2-Hydroxyglutarate Production, but Not Dominant Negative Function, Is Conferred by Glioma-Derived NADP-Dependent Isocitrate Dehydrogenase Mutations.
  PLoS One, 6, e16812.  
20849810 G.Solaini, G.Sgarbi, and A.Baracca (2011).
Oxidative phosphorylation in cancer cells.
  Biochim Biophys Acta, 1807, 534-542.  
20473936 G.Toedt, S.Barbus, M.Wolter, J.Felsberg, B.Tews, F.Blond, M.C.Sabel, S.Hofmann, N.Becker, C.Hartmann, H.Ohgaki, A.von Deimling, O.D.Wiestler, M.Hahn, P.Lichter, G.Reifenberger, and B.Radlwimmer (2011).
Molecular signatures classify astrocytic gliomas by IDH1 mutation status.
  Int J Cancer, 128, 1095-1103.  
20629098 H.M.Lin, N.A.Helsby, D.D.Rowan, and L.R.Ferguson (2011).
Using metabolomic analysis to understand inflammatory bowel diseases.
  Inflamm Bowel Dis, 17, 1021-1029.  
20725730 I.F.Pollack, R.L.Hamilton, R.W.Sobol, M.N.Nikiforova, M.A.Lyons-Weiler, W.A.Laframboise, P.C.Burger, D.J.Brat, M.K.Rosenblum, E.J.Holmes, T.Zhou, and R.I.Jakacki (2011).
IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group.
  Childs Nerv Syst, 27, 87-94.  
21386834 I.J.Majewski, and R.Bernards (2011).
Taming the dragon: genomic biomarkers to individualize the treatment of cancer.
  Nat Med, 17, 304-312.  
  21403835 J.Kurhanewicz, D.B.Vigneron, K.Brindle, E.Y.Chekmenev, A.Comment, C.H.Cunningham, R.J.Deberardinis, G.G.Green, M.O.Leach, S.S.Rajan, R.R.Rizi, B.D.Ross, W.S.Warren, and C.R.Malloy (2011).
Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research.
  Neoplasia, 13, 81-97.  
21383741 J.R.Prensner, and A.M.Chinnaiyan (2011).
Metabolism unhinged: IDH mutations in cancer.
  Nat Med, 17, 291-293.  
20962861 K.Yoshida, M.Sanada, M.Kato, R.Kawahata, A.Matsubara, J.Takita, L.Y.Shih, H.Mori, H.P.Koeffler, and S.Ogawa (2011).
A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders.
  Leukemia, 25, 184-186.  
22057236 M.F.Amary, S.Damato, D.Halai, M.Eskandarpour, F.Berisha, F.Bonar, S.McCarthy, V.R.Fantin, K.S.Straley, S.Lobo, W.Aston, C.L.Green, R.E.Gale, R.Tirabosco, A.Futreal, P.Campbell, N.Presneau, and A.M.Flanagan (2011).
Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2.
  Nat Genet, 43, 1262-1265.  
21878982 M.G.Vander Heiden (2011).
Targeting cancer metabolism: a therapeutic window opens.
  Nat Rev Drug Discov, 10, 671-684.  
21352804 M.K.Kaneko, W.Tian, S.Takano, H.Suzuki, Y.Sawa, Y.Hozumi, K.Goto, K.Yamazaki, C.Kitanaka, and Y.Kato (2011).
Establishment of a novel monoclonal antibody SMab-1 specific for IDH1-R132S mutation.
  Biochem Biophys Res Commun, 406, 608-613.  
21250968 M.M.Pichler, C.Bodner, C.Fischer, A.J.Deutsch, K.Hiden, C.Beham-Schmid, W.Linkesch, C.Guelly, H.Sill, and A.Wölfler (2011).
Evaluation of mutations in the isocitrate dehydrogenase genes in therapy-related and secondary acute myeloid leukaemia identifies a patient with clonal evolution to IDH2 R172K homozygosity due to uniparental disomy.
  Br J Haematol, 152, 669-672.  
20615753 N.K.Kloosterhof, L.B.Bralten, H.J.Dubbink, P.J.French, and M.J.van den Bent (2011).
Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma?
  Lancet Oncol, 12, 83-91.  
21258394 R.A.Cairns, I.S.Harris, and T.W.Mak (2011).
Regulation of cancer cell metabolism.
  Nat Rev Cancer, 11, 85-95.  
21460794 R.Chowdhury, K.K.Yeoh, Y.M.Tian, L.Hillringhaus, E.A.Bagg, N.R.Rose, I.K.Leung, X.S.Li, E.C.Woon, M.Yang, M.A.McDonough, O.N.King, I.J.Clifton, R.J.Klose, T.D.Claridge, P.J.Ratcliffe, C.J.Schofield, and A.Kawamura (2011).
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
  EMBO Rep, 12, 463-469.
PDB codes: 2ybk 2ybp 2ybs 2yc0 2yde
20820872 R.Ferrer-Luna, L.Núñez, J.Piquer, E.Arias, F.Dasí, A.Cervio, N.Arakaki, G.Sevlever, B.Celda, and H.Martinetto (2011).
Whole-genomic survey of oligodendroglial tumors: correlation between allelic imbalances and gene expression profiles.
  J Neurooncol, 103, 71-85.  
20727073 S.Brehmer, S.Pusch, K.Schmieder, A.von Deimling, and C.Hartmann (2011).
Mutational analysis of D2HGDH and L2HGDH in brain tumours without IDH1 or IDH2 mutations.
  Neuropathol Appl Neurobiol, 37, 330-332.  
21181477 S.C.Williams, M.A.Karajannis, L.Chiriboga, J.G.Golfinos, A.von Deimling, and D.Zagzag (2011).
R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma.
  Acta Neuropathol, 121, 279-281.  
20962862 S.Soverini, J.Score, I.Iacobucci, A.Poerio, A.Lonetti, A.Gnani, S.Colarossi, A.Ferrari, F.Castagnetti, G.Rosti, F.Cervantes, A.Hochhaus, M.Delledonne, A.Ferrarini, M.Sazzini, D.Luiselli, M.Baccarani, N.C.Cross, and G.Martinelli (2011).
IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis.
  Leukemia, 25, 178-181.  
21344322 S.Takano, W.Tian, M.Matsuda, T.Yamamoto, E.Ishikawa, M.K.Kaneko, K.Yamazaki, Y.Kato, and A.Matsumura (2011).
Detection of IDH1 mutation in human gliomas: comparison of immunohistochemistry and sequencing.
  Brain Tumor Pathol, 28, 115-123.  
22057234 T.C.Pansuriya, R.van Eijk, P.d'Adamo, M.A.van Ruler, M.L.Kuijjer, J.Oosting, A.M.Cleton-Jansen, J.G.van Oosterwijk, S.L.Verbeke, D.Meijer, T.van Wezel, K.H.Nord, L.Sangiorgi, B.Toker, B.Liegl-Atzwanger, M.San-Julian, R.Sciot, N.Limaye, L.G.Kindblom, S.Daugaard, C.Godfraind, L.M.Boon, M.Vikkula, K.C.Kurek, K.Szuhai, P.J.French, and J.V.Bovée (2011).
Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome.
  Nat Genet, 43, 1256-1261.  
  21356389 T.Shibata, A.Kokubu, M.Miyamoto, Y.Sasajima, and N.Yamazaki (2011).
Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation.
  Am J Pathol, 178, 1395-1402.  
21079611 W.C.Chou, W.C.Lei, B.S.Ko, H.A.Hou, C.Y.Chen, J.L.Tang, M.Yao, W.Tsay, S.J.Wu, S.Y.Huang, S.C.Hsu, Y.C.Chen, Y.C.Chang, K.T.Kuo, F.Y.Lee, M.C.Liu, C.W.Liu, M.H.Tseng, C.F.Huang, and H.F.Tien (2011).
The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia.
  Leukemia, 25, 246-253.  
21508971 W.H.Koppenol, P.L.Bounds, and C.V.Dang (2011).
Otto Warburg's contributions to current concepts of cancer metabolism.
  Nat Rev Cancer, 11, 325-337.  
21399634 X.J.Yan, J.Xu, Z.H.Gu, C.M.Pan, G.Lu, Y.Shen, J.Y.Shi, Y.M.Zhu, L.Tang, X.W.Zhang, W.X.Liang, J.Q.Mi, H.D.Song, K.Q.Li, Z.Chen, and S.J.Chen (2011).
Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia.
  Nat Genet, 43, 309-315.  
21289278 Z.J.Reitman, G.Jin, E.D.Karoly, I.Spasojevic, J.Yang, K.W.Kinzler, Y.He, D.D.Bigner, B.Vogelstein, and H.Yan (2011).
Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.
  Proc Natl Acad Sci U S A, 108, 3270-3275.  
20071234 A.B.Grossman (2010).
Where metabolism meets oncogenesis: another false lead?
  Lancet Oncol, 11, 309-310.  
20965423 A.J.Majmundar, W.J.Wong, and M.C.Simon (2010).
Hypoxia-inducible factors and the response to hypoxic stress.
  Mol Cell, 40, 294-309.  
20410924 A.Pardanani, T.L.Lasho, C.M.Finke, M.Mai, R.F.McClure, and A.Tefferi (2010).
IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms.
  Leukemia, 24, 1146-1151.  
20428194 A.Tefferi (2010).
Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.
  Leukemia, 24, 1128-1138.  
20508616 A.Tefferi, T.L.Lasho, O.Abdel-Wahab, P.Guglielmelli, J.Patel, D.Caramazza, L.Pieri, C.M.Finke, O.Kilpivaara, M.Wadleigh, M.Mai, R.F.McClure, D.G.Gilliland, R.L.Levine, A.Pardanani, and A.M.Vannucchi (2010).
IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.
  Leukemia, 24, 1302-1309.  
20975740 B.Yang, C.Zhong, Y.Peng, Z.Lai, and J.Ding (2010).
Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H.
  Cell Res, 20, 1188-1200.
PDB codes: 3map 3mar 3mas
21088844 C.Hartmann, B.Hentschel, W.Wick, D.Capper, J.Felsberg, M.Simon, M.Westphal, G.Schackert, R.Meyermann, T.Pietsch, G.Reifenberger, M.Weller, M.Loeffler, and A.von Deimling (2010).
Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas.
  Acta Neuropathol, 120, 707-718.  
  20431032 C.Horbinski, L.Kelly, Y.E.Nikiforov, M.B.Durso, and M.N.Nikiforova (2010).
Detection of IDH1 and IDH2 mutations by fluorescence melting curve analysis as a diagnostic tool for brain biopsies.
  J Mol Diagn, 12, 487-492.  
20651067 C.L.Green, C.M.Evans, R.K.Hills, A.K.Burnett, D.C.Linch, and R.E.Gale (2010).
The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status.
  Blood, 116, 2779-2782.  
20454987 D.D.Pollak, N.Bae, G.Mostafa, and H.Hoeger (2010).
Strain-dependent expression of metabolic proteins in the mouse hippocampus.
  Amino Acids, 39, 1451-1462.  
20703252 D.K.Nomura, M.M.Dix, and B.F.Cravatt (2010).
Activity-based protein profiling for biochemical pathway discovery in cancer.
  Nat Rev Cancer, 10, 630-638.  
20090720 E.C.Hayden (2010).
Genomics boosts brain-cancer work.
  Nature, 463, 278.  
  20463368 E.D.Michelakis, G.Sutendra, P.Dromparis, L.Webster, A.Haromy, E.Niven, C.Maguire, T.L.Gammer, J.R.Mackey, D.Fulton, B.Abdulkarim, M.S.McMurtry, and K.C.Petruk (2010).
Metabolic modulation of glioblastoma with dichloroacetate.
  Sci Transl Med, 2, 31ra34.  
  20445000 E.G.Van Meir, C.G.Hadjipanayis, A.D.Norden, H.K.Shu, P.Y.Wen, and J.J.Olson (2010).
Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma.
  CA Cancer J Clin, 60, 166-193.  
20127344 F.E.Bleeker, N.A.Atai, S.Lamba, A.Jonker, D.Rijkeboer, K.S.Bosch, W.Tigchelaar, D.Troost, W.P.Vandertop, A.Bardelli, and C.J.Van Noorden (2010).
The prognostic IDH1( R132 ) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma.
  Acta Neuropathol, 119, 487-494.  
20797612 F.Kopp, T.Komatsu, D.K.Nomura, S.A.Trauger, J.R.Thomas, G.Siuzdak, G.M.Simon, and B.F.Cravatt (2010).
The glycerophospho metabolome and its influence on amino acid homeostasis revealed by brain metabolomics of GDE1(-/-) mice.
  Chem Biol, 17, 831-840.  
20393534 H.Ledford (2010).
Big science: The cancer genome challenge.
  Nature, 464, 972-974.  
20399149 H.Noushmehr, D.J.Weisenberger, K.Diefes, H.S.Phillips, K.Pujara, B.P.Berman, F.Pan, C.E.Pelloski, E.P.Sulman, K.P.Bhat, R.G.Verhaak, K.A.Hoadley, D.N.Hayes, C.M.Perou, H.K.Schmidt, L.Ding, R.K.Wilson, D.Van Den Berg, H.Shen, H.Bengtsson, P.Neuvial, L.M.Cope, J.Buckley, J.G.Herman, S.B.Baylin, P.W.Laird, and K.Aldape (2010).
Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma.
  Cancer Cell, 17, 510-522.  
20714783 I.Yang, and L.M.Liau (2010).
American Association for Cancer Research Genetics and Biology of Brain Cancers 2009, December 13-15, 2009, San Diego, CA.
  J Neurooncol, 99, 297-306.  
20131059 J.Felsberg, M.Wolter, H.Seul, B.Friedensdorf, M.Göppert, M.C.Sabel, and G.Reifenberger (2010).
Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing.
  Acta Neuropathol, 119, 501-507.  
20678218 J.Rocquain, N.Carbuccia, V.Trouplin, S.Raynaud, A.Murati, M.Nezri, Z.Tadrist, S.Olschwang, N.Vey, D.Birnbaum, V.Gelsi-Boyer, and M.J.Mozziconacci (2010).
Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias.
  BMC Cancer, 10, 401.  
20414201 J.T.Huse, and E.C.Holland (2010).
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma.
  Nat Rev Cancer, 10, 319-331.  
20972461 K.E.Yen, M.A.Bittinger, S.M.Su, and V.R.Fantin (2010).
Cancer-associated IDH mutations: biomarker and therapeutic opportunities.
  Oncogene, 29, 6409-6417.  
20829819 K.Garber (2010).
Oncology's energetic pipeline.
  Nat Biotechnol, 28, 888-891.  
20692206 L.Dang, S.Jin, and S.M.Su (2010).
IDH mutations in glioma and acute myeloid leukemia.
  Trends Mol Med, 16, 387-397.  
20659156 L.Sellner, D.Capper, J.Meyer, C.D.Langhans, C.M.Hartog, H.Pfeifer, H.Serve, A.D.Ho, J.G.Okun, A.Krämer, and A.Von Deimling (2010).
Increased levels of 2-hydroxyglutarate in AML patients with IDH1-R132H and IDH2-R140Q mutations.
  Eur J Haematol, 85, 457-459.  
20534697 M.Andrulis, D.Capper, J.Meyer, R.Penzel, C.Hartmann, H.Zentgraf, and A.von Deimling (2010).
IDH1 R132H mutation is a rare event in myeloproliferative neoplasms as determined by a mutation specific antibody.
  Haematologica, 95, 1797-1798.  
20884716 M.Cazzola (2010).
IDH1 and IDH2 mutations in myeloid neoplasms--novel paradigms and clinical implications.
  Haematologica, 95, 1623-1627.  
20042721 M.J.Dyer, T.Akasaka, M.Capasso, P.Dusanjh, Y.F.Lee, E.L.Karran, I.Nagel, I.Vater, G.Cario, and R.Siebert (2010).
Immunoglobulin heavy chain locus chromosomal translocations in B-cell precursor acute lymphoblastic leukemia: rare clinical curios or potent genetic drivers?
  Blood, 115, 1490-1499.  
20714900 M.J.Riemenschneider, J.W.Jeuken, P.Wesseling, and G.Reifenberger (2010).
Molecular diagnostics of gliomas: state of the art.
  Acta Neuropathol, 120, 567-584.  
20610347 M.Jansen, S.Yip, and D.N.Louis (2010).
Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers.
  Lancet Neurol, 9, 717-726.  
20847235 M.Kranendijk, E.A.Struys, E.van Schaftingen, K.M.Gibson, W.A.Kanhai, M.S.van der Knaap, J.Amiel, N.R.Buist, A.M.Das, Klerk, A.S.Feigenbaum, D.K.Grange, F.C.Hofstede, E.Holme, E.P.Kirk, S.H.Korman, E.Morava, A.Morris, J.Smeitink, R.N.Sukhai, H.Vallance, C.Jakobs, and G.S.Salomons (2010).
IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.
  Science, 330, 336.  
20465388 M.Labussiere, X.W.Wang, A.Idbaih, F.Ducray, and M.Sanson (2010).
Prognostic markers in gliomas.
  Future Oncol, 6, 733-739.  
20514489 M.Seiz, J.Tuettenberg, J.Meyer, M.Essig, K.Schmieder, C.Mawrin, A.von Deimling, and C.Hartmann (2010).
Detection of IDH1 mutations in gliomatosis cerebri, but only in tumors with additional solid component: evidence for molecular subtypes.
  Acta Neuropathol, 120, 261-267.  
20919826 M.Weller, W.Wick, M.E.Hegi, R.Stupp, and G.Tabatabai (2010).
Should biomarkers be used to design personalized medicine for the treatment of glioblastoma?
  Future Oncol, 6, 1407-1414.  
20962328 N.Bhagwat, and R.L.Levine (2010).
Metabolic syndromes and malignant transformation: where the twain shall meet.
  Sci Transl Med, 2, 54ps50.  
20368582 O.Abdel-Wahab, and R.L.Levine (2010).
Metabolism and the leukemic stem cell.
  J Exp Med, 207, 677-680.  
20734021 P.Dromparis, G.Sutendra, and E.D.Michelakis (2010).
The role of mitochondria in pulmonary vascular remodeling.
  J Mol Med, 88, 1003-1010.  
20171147 P.S.Ward, J.Patel, D.R.Wise, O.Abdel-Wahab, B.D.Bennett, H.A.Coller, J.R.Cross, V.R.Fantin, C.V.Hedvat, A.E.Perl, J.D.Rabinowitz, M.Carroll, S.M.Su, K.A.Sharp, R.L.Levine, and C.B.Thompson (2010).
The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.
  Cancer Cell, 17, 225-234.  
20528226 R.J.DeBerardinis (2010).
2010 keystone symposium: metabolism and cancer progression.
  Future Oncol, 6, 893-895.  
20305482 R.J.Komotar, R.M.Starke, M.B.Sisti, and E.S.Connolly (2010).
IDH1 and IDH2 mutations in gliomas and the associated induction of hypoxia-inducible factor and production of 2-hydroxyglutarate.
  Neurosurgery, 66, N20-N21.  
20690818 S.E.Calvo, and V.K.Mootha (2010).
The mitochondrial proteome and human disease.
  Annu Rev Genomics Hum Genet, 11, 25-44.  
20142433 S.Gross, R.A.Cairns, M.D.Minden, E.M.Driggers, M.A.Bittinger, H.G.Jang, M.Sasaki, S.Jin, D.P.Schenkein, S.M.Su, L.Dang, V.R.Fantin, and T.W.Mak (2010).
Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations.
  J Exp Med, 207, 339-344.  
20809335 S.Hofer, and A.B.Lassman (2010).
Molecular markers in gliomas: impact for the clinician.
  Target Oncol, 5, 201-210.  
21127243 S.L.McKnight (2010).
On getting there from here.
  Science, 330, 1338-1339.  
20805365 S.Schnittger, C.Haferlach, M.Ulke, T.Alpermann, W.Kern, and T.Haferlach (2010).
IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status.
  Blood, 116, 5486-5496.  
21045797 T.D.Bourne, and D.Schiff (2010).
Update on molecular findings, management and outcome in low-grade gliomas.
  Nat Rev Neurol, 6, 695-701.  
  20181022 T.N.Seyfried, and L.M.Shelton (2010).
Cancer as a metabolic disease.
  Nutr Metab (Lond), 7, 7.  
20973793 W.G.Kaelin (2010).
New cancer targets emerging from studies of the Von Hippel-Lindau tumor suppressor protein.
  Ann N Y Acad Sci, 1210, 1-7.  
20367200 Y.Sonoda, and T.Tominaga (2010).
2-hydroxyglutarate accumulation caused by IDH mutation is involved in the formation of malignant gliomas.
  Expert Rev Neurother, 10, 487-489.  
20513808 Z.J.Reitman, and H.Yan (2010).
Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism.
  J Natl Cancer Inst, 102, 932-941.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.