The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

被引：809

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

共 31 条

[1] Structural insights into histone demethylation by JMJD2 family members
Chen, Zhongzhou
Zang, Jianye
Whetstine, Johnathan
Hong, Xia
Davrazou, Foteini
Kutateladze, Tatiana G.
Simpson, Michael
Mao, Qilong
Pan, Cheol-Ho
Dai, Shaodong
Hagman, James
Hansen, Kirk
Shi, Yang
Zhang, Gongyi
[J]. CELL, 2006, 125 (04) : 691 - 702
[2] Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases
Chowdhury, Rasheduzzaman
McDonough, Michael A.
Mecinovic, Jasmin
Loenarz, Christoph
Flashman, Emily
Hewitson, Kirsty S.
Domene, Carmen
Schofield, Christopher J.
[J]. STRUCTURE, 2009, 17 (07) : 981 - 989
[3] Structural basis for binding of cyclic 2-oxoglutarate analogues to factor-inhibiting hypoxia-inducible factor
Conejo-Garcia, Ana
McDonough, Michael A.
Loenarz, Christoph
McNeill, Luke A.
Hewitson, Kirsty S.
Ge, Wei
Lienard, Benoit M.
Schofield, Christopher J.
Clifton, Ian J.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (20) : 6125 - 6128
[4] Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase
Couture, Jean-Francois
Collazo, Evys
Ortiz-Tello, Patricia A.
Brunzelle, Joseph S.
Trievel, Raymond C.
[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2007, 14 (08) : 689 - 695
[5] Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes
Dalgliesh, Gillian L.
Furge, Kyle
Greenman, Chris
Chen, Lina
Bignell, Graham
Butler, Adam
Davies, Helen
Edkins, Sarah
Hardy, Claire
Latimer, Calli
Teague, Jon
Andrews, Jenny
Barthorpe, Syd
Beare, Dave
Buck, Gemma
Campbell, Peter J.
Forbes, Simon
Jia, Mingming
Jones, David
Knott, Henry
Kok, Chai Yin
Lau, King Wai
Leroy, Catherine
Lin, Meng-Lay
McBride, David J.
Maddison, Mark
Maguire, Simon
McLay, Kirsten
Menzies, Andrew
Mironenko, Tatiana
Mulderrig, Lee
Mudie, Laura
O'Meara, Sarah
Pleasance, Erin
Rajasingham, Arjunan
Shepherd, Rebecca
Smith, Raffaella
Stebbings, Lucy
Stephens, Philip
Tang, Gurpreet
Tarpey, Patrick S.
Turrell, Kelly
Dykema, Karl J.
Khoo, Sok Kean
Petillo, David
Wondergem, Bill
Anema, John
Kahnoski, Richard J.
Teh, Bin Tean
Stratton, Michael R.
[J]. NATURE, 2010, 463 (7279) : 360 - 363
[6] IDH mutations in glioma and acute myeloid leukemia
Dang, Lenny
Jin, Shengfang
Su, Shinsan M.
[J]. TRENDS IN MOLECULAR MEDICINE, 2010, 16 (09) : 387 - 397
[7] Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, Lenny
White, David W.
Gross, Stefan
Bennett, Bryson D.
Bittinger, Mark A.
Driggers, Edward M.
Fantin, Valeria R.
Jang, Hyun Gyung
Jin, Shengfang
Keenan, Marie C.
Marks, Kevin M.
Prins, Robert M.
Ward, Patrick S.
Yen, Katharine E.
Liau, Linda M.
Rabinowitz, Joshua D.
Cantley, Lewis C.
Thompson, Craig B.
Heiden, Matthew G. Vander
Su, Shinsan M.
[J]. NATURE, 2009, 462 (7274) : 739 - U52
[8] Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1α
Elkins, JM
Hewitson, KS
McNeill, LA
Seibel, JF
Schlemminger, I
Pugh, CW
Ratcliffe, PJ
Schofield, CJ
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (03) : 1802 - 1806
[9] JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes
Frescas, David
Guardavaccaro, Daniele
Bassermann, Florian
Koyama-Nasu, Ryo
Pagano, Michele
[J]. NATURE, 2007, 450 (7167) : 309 - U17
[10] Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations
Gross, Stefan
Cairns, Rob A.
Minden, Mark D.
Driggers, Edward M.
Bittinger, Mark A.
Jang, Hyun Gyung
Sasaki, Masato
Jin, Shengfang
Schenkein, David P.
Su, Shinsan M.
Dang, Lenny
Fantin, Valeria R.
Mak, Tak W.
[J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2010, 207 (02) : 339 - 344

← 1 2 3 4 →