Berger, Raffaela S. and Wachsmuth, Christian J. and Waldhier, Magdalena C. and Renner-Sattler, Kathrin and Thomas, Simone and Chaturvedi, Anuhar and Niller, Hans-Helmut and Bumes, Elisabeth and Hau, Peter and Proescholdt, Martin and Gronwald, Wolfram and Heuser, Michael and Kreutz, Marina and Oefner, Peter J. and Dettmer, Katja (2021) Lactonization of the Oncometabolite D-2-Hydroxyglutarate Produces a Novel Endogenous Metabolite. CANCERS, 13 (8): 1756. ISSN , 2072-6694
Full text not available from this repository. (Request a copy)Abstract
Simple Summary Somatic mutations in isocitrate dehydrogenase give rise to the excessive production and accumulation of D-2-hydroxyglutarate in certain malignancies. In addition to this well-described oncometabolite, we discovered a chemically related metabolite, namely 2-hydroxyglutarate-gamma-lactone, which is derived directly from 2-hydroxyglutarate. This novel metabolite may impact the anti-tumor immune response. In recent years, onco-metabolites like D-2-hydroxyglutarate, which is produced in isocitrate dehydrogenase-mutated tumors, have gained increasing interest. Here, we report a metabolite in human specimens that is closely related to 2-hydroxyglutarate: the intramolecular ester of 2-hydroxyglutarate, 2-hydroxyglutarate-gamma-lactone. Using C-13(5)-L-glutamine tracer analysis, we showed that 2-hydroxyglutarate is the endogenous precursor of 2-hydroxyglutarate-lactone and that there is a high exchange between these two metabolites. Lactone formation does not depend on mutated isocitrate dehydrogenase, but its formation is most probably linked to transport processes across the cell membrane and favored at low environmental pH. Furthermore, human macrophages showed not only striking differences in uptake of 2-hydroxyglutarate and its lactone but also in the enantiospecific hydrolysis of the latter. Consequently, 2-hydroxyglutarate-lactone may play a critical role in the modulation of the tumor microenvironment.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; PRESSURE CHEMICAL-IONIZATION; ISOCITRATE DEHYDROGENASE MUTATIONS; FLIGHT MASS-SPECTROMETRY; IDH2 MUTATIONS; 2-HYDROXYGLUTARATE; DEGRADATION; DERIVATIVES; DISEASE; ACID; D-2-hydroxyglutarate; IDH1; 2 mutation; lactonization; acute myeloid leukemia |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Medicine > Lehrstuhl für Neurochirurgie Medicine > Lehrstuhl für Neurologie Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Aug 2022 07:18 |
| Last Modified: | 02 Aug 2022 07:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/45978 |
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