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.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Shanghai Medical School, Fudan University, Shanghai 20032, China.
Wei
W
Xu
Hui
H
Yang
Ying
Y
Liu
Ying
Y
Yang
Ping
P
Wang
Se-Hee
SH
Kim
Shinsuke
S
Ito
Chen
C
Yang
Pu
P
Wang
Meng-Tao
MT
Xiao
Li-xia
LX
Liu
Wen-qing
WQ
Jiang
Jing
J
Liu
Jin-ye
JY
Zhang
Bin
B
Wang
Stephen
S
Frye
Yi
Y
Zhang
Yan-hui
YH
Xu
Qun-ying
QY
Lei
Kun-Liang
KL
Guan
Shi-min
SM
Zhao
Yue
Y
Xiong
D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D001667:Binding, Competitive; D055162:Biocatalysis / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000201:enzymology; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043169:Endostatins / Q000378:metabolism; D044783:F-Box Proteins; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005977:Glutarates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006899:Mixed Function Oxygenases; D008958:Models, Molecular; D010070:Oxalates / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D043169:Endostatins; D044783:F-Box Proteins; D005977:Glutarates; C497442:HIF1A protein, human; D006657:Histones; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D010070:Oxalates; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; C088144:HoxA protein; C019417:alpha-hydroxyglutarate; C015407:oxalomalic acid; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D056466:Histone Demethylases; C553255:JMJD-1.2 protein, C elegans; D056484:Jumonji Domain-Containing Histone Demethylases; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C534524:KDM2A protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010089:Oxidoreductases, N-Demethylating
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