Abstract
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 μM for the histone N(ɛ)-lysine demethylase JMJD2A to more than 5 mM 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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Crystallography
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Glutarates / metabolism*
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Histone Demethylases / antagonists & inhibitors*
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Humans
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Inhibitory Concentration 50
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Isocitrate Dehydrogenase / genetics*
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Isocitrate Dehydrogenase / metabolism
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
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Jumonji Domain-Containing Histone Demethylases / chemistry
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Magnetic Resonance Spectroscopy
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Mass Spectrometry
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Mixed Function Oxygenases
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Models, Molecular*
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Mutation / genetics
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Neoplasms / enzymology*
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Neoplasms / genetics
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Procollagen-Proline Dioxygenase / antagonists & inhibitors
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / chemistry
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Signal Transduction / physiology*
Substances
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Glutarates
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Repressor Proteins
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alpha-hydroxyglutarate
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Mixed Function Oxygenases
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Isocitrate Dehydrogenase
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HIF1AN protein, human
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Histone Demethylases
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Jumonji Domain-Containing Histone Demethylases
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Procollagen-Proline Dioxygenase
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KDM4A protein, human