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Pubmed ID :21251613
Publication Date : //

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


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.

Authors : Xu Wei , Yang Hui , Liu Ying , Yang Ying , Wang Ping , Kim Se-Hee , Ito Shinsuke , Yang Chen , Wang Pu , Xiao Meng-Tao , Liu Li-xia , Jiang Wen-qing , Liu Jing , Zhang Jin-ye , Wang Bin , Frye Stephen , Zhang Yi , Xu Yan-hui , Lei Qun-ying , Guan Kun-Liang , Zhao Shi-min , Xiong Yue ,

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