(S)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 (R)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 (R)-2-hydroxyglutarate + succinate semialdehyde <=> 2-oxoglutarate + 4-hydroxybutyrate 2-oxoglutarate + 4-hydroxybutyrate <=> (R)-2-hydroxyglutarate + succinate semialdehyde 2-oxoglutarate + NADPH + H+ => (R)-2-hydroxyglutarate + NADP+ [mutant IDH1] PathwayStep2174 PathwayStep2173 PathwayStep2172 PathwayStep2171 PathwayStep2170 Interconversion of 2-oxoglutarate and 2-hydroxyglutarate Authored: D'Eustachio, P, 2010-06-25 Edited: D'Eustachio, P, 2010-06-25 GENE ONTOLOGYGO:0006103 Pubmed16601864 Pubmed18772396 Pubmed19935646 Reactome Database ID Release 43880009 Reactome, http://www.reactome.org ReactomeREACT_25367 Reviewed: Jassal, B, 2010-11-09 Reviewed: Rush, MG, 2011-01-31 The two stereoisomers of 2-hydroxyglutarate are normally converted to 2-oxoglutarate in the mitochondrial matrix, and can then be metabolized by the citric acid cycle. The physiological sources of 2-hydroxyglutarate have not been established although plausible hypotheses are that it is generated by lysine breakdown or as a byproduct of delta-aminolevulinate metabolism. The stereoisomers are oxidized to 2-oxoglutarate in FAD-dependent reactions catalyzed by the enzymes D2HGDH (specific for R(-)-2-hydroxyglutarate) and L2HGDH (specific for S(-)-2-hydroxyglutarate). An inherited deficiency in either enzyme is associated with accumulation of 2-hydroxyglutarate and variable neurological symptoms. R(-)-2-hydroxyglutarate also reacts reversibly with succinate semialdehyde to form 4-hydroxybutyrate and 2-oxoglutarate, catalyzed by ADHFE1. No deficiencies of this enzyme have been found in patients with elevated 2-hydroxyglutarate levels (Struys 2006).<p>Somatic mutations affecting arginine residue 132 of IDH1 (isocitrate dehydrogenase 1, a cytosolic enzyme that normally catalyzes the NADP+-dependent conversion of isocitrate to 2-oxoglutarate), are very commonly found in human glioblastomas (Parsons et al. 2008). These mutant proteins efficiently catalyze the NADPH-dependent reduction of 2-oxoglutarate to form 2-hydroxyglutarate. Cells expressing the mutant protein accumulate elevated levels of 2-hydroxyglutarate, probably in the cytosol as IDH1 is a cytosolic enzyme. The fate of the 2-hydroxyglutarate is unclear, but the high frequency with which the mutation is found in surveys of primary tumors is consistent with the possibility that it is advantageous to the tumor cells (Dang et al 2009).