oxalomalic-acid and 5-hydroxymethylcytosine

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.

Topics: 5-Methylcytosine; Amino Acid Substitution; Animals; Binding, Competitive; Biocatalysis; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Catalytic Domain; Cell Line, Tumor; Cytosine; Dioxygenases; DNA-Binding Proteins; Endostatins; F-Box Proteins; Gene Expression; Glioma; Glutarates; Histone Demethylases; Histones; Homeodomain Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Isocitrate Dehydrogenase; Jumonji Domain-Containing Histone Demethylases; Ketoglutaric Acids; Mixed Function Oxygenases; Models, Molecular; Oxalates; Oxidoreductases, N-Demethylating; Procollagen-Proline Dioxygenase; Proto-Oncogene Proteins