title: Isocitrate dehydrogenase mutations in gliomas:  mechanisms, biomarkers and therapeutic target.
abstract: OBJECTIVE
  Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies.
  
  
  RESULTS
  Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth.
  
  
  CONCLUSIONS
  As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.
authors: The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute, Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors: Changcun
authors: C
authors: Guo
authors: Christopher J
authors: CJ
authors: Pirozzi
authors: Giselle Y
authors: GY
authors: Lopez
authors: Hai
authors: H
authors: Yan
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D005910:Glioma / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007523:Isocitrates / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D017354:Point Mutation; D011379:Prognosis; D011487:Protein Conformation
chemical_list: D015415:Biomarkers; D007523:Isocitrates; D007527:Isoenzymes; D007656:Ketoglutaric Acids; D007521:Isocitrate Dehydrogenase