Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases

Cancer Cell. 2011 Jan 18;19(1):17-30. doi: 10.1016/j.ccr.2010.12.014.

Abstract

IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism
  • Amino Acid Substitution / physiology
  • Animals
  • Binding, Competitive
  • Biocatalysis / drug effects
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / metabolism
  • Catalytic Domain
  • Cell Line, Tumor
  • Cytosine / analogs & derivatives
  • Cytosine / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dioxygenases / antagonists & inhibitors*
  • Dioxygenases / metabolism
  • Endostatins / metabolism
  • F-Box Proteins
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Glioma / enzymology*
  • Glioma / genetics
  • Glioma / metabolism
  • Glutarates / chemistry
  • Glutarates / metabolism
  • Glutarates / pharmacology*
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / metabolism
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
  • Jumonji Domain-Containing Histone Demethylases / chemistry
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Ketoglutaric Acids / chemistry
  • Ketoglutaric Acids / metabolism*
  • Ketoglutaric Acids / pharmacology
  • Mixed Function Oxygenases
  • Models, Molecular
  • Oxalates / pharmacology
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Oxidoreductases, N-Demethylating / metabolism
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Endostatins
  • F-Box Proteins
  • Glutarates
  • HIF1A protein, human
  • Histones
  • Homeodomain Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ketoglutaric Acids
  • Oxalates
  • Proto-Oncogene Proteins
  • TET2 protein, human
  • 5-hydroxymethylcytosine
  • HoxA protein
  • alpha-hydroxyglutarate
  • oxalomalic acid
  • 5-Methylcytosine
  • Cytosine
  • Mixed Function Oxygenases
  • TET1 protein, human
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human
  • Dioxygenases
  • Histone Demethylases
  • JMJD-1.2 protein, C elegans
  • Jumonji Domain-Containing Histone Demethylases
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • KDM2A protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Oxidoreductases, N-Demethylating

Associated data

  • PDB/3PUQ
  • PDB/3PUR