Reactome | Interconversion of 2-oxoglutarate and 2-hydroxyglutarate

Interconversion of 2-oxoglutarate and 2-hydroxyglutarate

Stable Identifier

R-HSA-880009

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Interconversion of 2-oxoglutarate and 2-hydroxyglutarate

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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