The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

被引：782

作者：

Chowdhury, Rasheduzzaman ^{[1
]}

Yeoh, Kar Kheng ^{[1
]}

Tian, Ya-Min ^{[2
]}

Hillringhaus, Lars ^{[1
]}

Bagg, Eleanor A. ^{[1
]}

Rose, Nathan R. ^{[1
]}

Leung, Ivanhoe K. H. ^{[1
]}

Li, Xuan S. ^{[3
]}

Woon, Esther C. Y. ^{[1
]}

Yang, Ming ^{[1
]}

McDonough, Michael A. ^{[1
]}

King, Oliver N. ^{[1
]}

Clifton, Ian J. ^{[1
]}

Klose, Robert J. ^{[3
]}

Claridge, Timothy D. W. ^{[1
]}

Ratcliffe, Peter J. ^{[2
]}

Schofield, Christopher J. ^{[1
]}

Kawamura, Akane ^{[1
]}

机构：

[1] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England

[2] Univ Oxford, Dept Clin Med, Oxford OX3 7BN, England

[3] Univ Oxford, Dept Biochem, Epigenet Regulat Chromatin Funct Grp, Oxford OX1 3QU, England

来源：

EMBO REPORTS | 2011年 / 12卷 / 05期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

isocitrate dehydrogenase; 2-hydroxyglutarate; 2-oxoglutarate; oxygenases; hypoxia-inducible factor; HYPOXIA-INDUCIBLE FACTOR; ISOCITRATE DEHYDROGENASE 1; PROLYL HYDROXYLASE; STRUCTURAL BASIS; MUTATIONS; CANCER; TRANSCRIPTION; SPECIFICITY; HIF-1-ALPHA; METABOLISM;

D O I：

10.1038/embor.2011.43

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mutations in isocitrate dehydrogenases (IDHs) have a gain-of- function effect leading to R(-)-2-hydroxyglutarate (R-2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R-and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies. Half-maximal inhibitory concentration (IC(50)) values for the R-form of 2HG varied from approximately 25 mu M for the histone N(epsilon)-lysine demethylase JMJD2A to more than 5mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH-associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation.

引用

页码：463 / 469

页数：7

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