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

W Xu, H Yang, Y Liu, Y Yang, P Wang, SH Kim, S Ito… - Cancer cell, 2011 - cell.com
W Xu, H Yang, Y Liu, Y Yang, P Wang, SH Kim, S Ito, C Yang, P Wang, MT Xiao, L Liu…
Cancer cell, 2011cell.com
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 …
Summary
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.
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