α-Hydroxyglutaric acid is normally metabolized to 2-oxoglutarate by D- and L-2-hydroxyglutarate dehydrogenases. Mutations in these enzymes cause 2-hydroxyglutaric aciduria, a neurometabolic disorder.1,2,3 Recent studies have found that mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2, typically associated with certain cancers, can cause these enzymes to convert isocitrate to 2-HG, rather than α-ketoglutarate.4,5 2-HG is structurally similar to α-ketoglutarate and competitively inhibits α-ketoglutarate-dependent dioxygenases, including lysine demethylases and DNA hydroxylases.5,6,7 (2R)-Octyl-α-hydroxyglutarate-d17 is intended for use as an internal standard for the quantification of (2R)-octyl-α-hydroxyglutarate by GC- or LC-MS. (2R)-Octyl-α-hydroxyglutarate is a cell-permeable derivative of the D-isomer of 2-HG. It has been used to examine the contribution of D-2-HG to the oxidative mitochondrial processes of IDH1-mutated cancer cells.8
1.Rzem, R., Veiga-da-Cunha, M., NoËl, G., et al.A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduriaProc. Nat. Acad. Sci. USA101(48)16849-16854(2004) 2.Struys, E.A., Verhoeven, N.M., Roos, B., et al.Disease-related metabolites in culture medium of fibroblasts from patients with D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, and combined D/L-2-hydroxyglutaric aciduriaClin. Chem.49(7)1133-1138(2003) 3.Struys, E.A., Salomons, G.S., Achouri, Y., et al.Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduriaAmerican Journal of Human Genetics76(2)358-360(2005) 4.Ward, P., Patel, J., Wise, D.R., et al.The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarateCancer Cell17225-234(2010) 5.Yang, H., Ye, D., Guan, K.L., et al.IDH1 and IDH2 mutations in tumorigenesis: Mechanistic insights and clinical perspectivesClin. Cancer Res.18(20)5562-5571(2012) 6.Xu, W., Yang, H., Liu, Y., et al.Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenasesCancer Cell19(1)17-30(2011) 7.Chowdhury, R., Yeoh, K.K., Tian, Y.M., et al.The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylasesEMBO Rep.12(5)463-469(2011) 8.Reitman, Z.J., Duncan, C.G., Poteet, E., et al.Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxiaThe Journal of Biological Chemisty289(34)23318-23328(2014)