Interconversion of 2-oxoglutarate and 2-hydroxyglutarate

Stable Identifier
Homo sapiens
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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).
Literature References
PubMed ID Title Journal Year
19935646 Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Keenan, MC, White, DW, Su, SM, Liau, LM, Yen, KE, Bittinger, MA, Gross, S, Fantin, VR, Dang, L, Thompson, CB, Jin, S, Cantley, LC, Rabinowitz, JD, Ward, PS, Bennett, BD, Jang, HG, Marks, KM, Prins, RM, Vander Heiden, MG, Driggers, EM

Nature 2009
18772396 An integrated genomic analysis of human glioblastoma multiforme

Bigner, DD, McLendon, R, Gallia, GL, Strausberg, RL, Karchin, R, Mankoo, P, Papadopoulos, N, Marie, SK, Parsons, DW, Hartigan, J, Kinzler, KW, Nikolsky, Y, Vogelstein, B, Diaz Jr, LA, Angenendt, P, Shinjo, SM, Velculescu, VE, Lin, JC, Jones, S, Parmigiani, G, Zhang, X, Leary, RJ, Yan, H, Smith, DR, Nikolskaya, T, Riggins, GJ, Keir, S, Olivi, A, Rasheed, BA, Siu, IM, Carter, H, Tekleab, H, Busam, DA

Science 2008
16601864 D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect

Struys, EA

J Inherit Metab Dis 2006
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