Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.
Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.
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DOI：
10.1016/j.ccr.2010.12.014
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发表时间：
2011-01-18
期刊：
影响因子：
50.3
通讯作者：
Xiong Y
中科院分区：
文献类型：
--
作者：
Xu W;Yang H;Liu Y;Yang Y;Wang P;Kim SH;Ito S;Yang C;Wang P;Xiao MT;Liu LX;Jiang WQ;Liu J;Zhang JY;Wang B;Frye S;Zhang Y;Xu YH;Lei QY;Guan KL;Zhao SM;Xiong Y
IDH1和IDH2突变在胶质瘤和急性髓系白血病中频繁发生，分别导致α-酮戊二酸（α-KG）生成活性的同时丧失以及2-羟基戊二酸（2 - HG）生成活性的增加。在此我们证明2 - HG是多种α - KG依赖的双加氧酶的竞争性抑制剂，包括组蛋白去甲基化酶和5 - 甲基胞嘧啶（5mC）羟化酶的TET家族。2 - HG在组蛋白去甲基化酶的活性位点占据与α - KG相同的空间。肿瘤来源的IDH1和IDH2突变体的异位表达抑制组蛋白去甲基化和5mC羟化。在胶质瘤中，IDH1突变与组蛋白甲基化增加和5 - 羟甲基胞嘧啶（5hmC）减少相关。因此，肿瘤来源的IDH1和IDH2突变减少α - KG并积累一种α - KG拮抗剂2 - HG，导致全基因组组蛋白和DNA甲基化改变。
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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影响因子：
64.5
作者：
Chen, Zhongzhou;Zang, Jianye;Zhang, Gongyi
通讯作者：
Zhang, Gongyi
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
30.8
作者：
Langemeijer, Saskia M. C.;Kuiper, Roland P.;Jansen, Joop H.
通讯作者：
Jansen, Joop H.