The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
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 potencie...
| Auteurs principaux: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Langue: | English |
| Publié: |
2011
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| _version_ | 1826274716788195328 |
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| author | Chowdhury, R Yeoh, K Tian, Y Hillringhaus, L Bagg, E Rose, N Leung, I Li, X Woon, E Yang, M McDonough, M King, O Clifton, I Klose, R Claridge, T Ratcliffe, P Schofield, C Kawamura, A |
| author_facet | Chowdhury, R Yeoh, K Tian, Y Hillringhaus, L Bagg, E Rose, N Leung, I Li, X Woon, E Yang, M McDonough, M King, O Clifton, I Klose, R Claridge, T Ratcliffe, P Schofield, C Kawamura, A |
| author_sort | Chowdhury, R |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:47:42Z |
| format | Journal article |
| id | oxford-uuid:5dbd70c8-e943-4a4b-a941-a0b73080e416 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:47:42Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:5dbd70c8-e943-4a4b-a941-a0b73080e4162022-03-26T17:36:21ZThe oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5dbd70c8-e943-4a4b-a941-a0b73080e416EnglishSymplectic Elements at Oxford2011Chowdhury, RYeoh, KTian, YHillringhaus, LBagg, ERose, NLeung, ILi, XWoon, EYang, MMcDonough, MKing, OClifton, IKlose, RClaridge, TRatcliffe, PSchofield, CKawamura, AMutations 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. |
| spellingShingle | Chowdhury, R Yeoh, K Tian, Y Hillringhaus, L Bagg, E Rose, N Leung, I Li, X Woon, E Yang, M McDonough, M King, O Clifton, I Klose, R Claridge, T Ratcliffe, P Schofield, C Kawamura, A The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. |
| title | The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. |
| title_full | The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. |
| title_fullStr | The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. |
| title_full_unstemmed | The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. |
| title_short | The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. |
| title_sort | oncometabolite 2 hydroxyglutarate inhibits histone lysine demethylases |
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