Description
α-Hydroxyglutaric acid (2-HG; ) 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 Octyl-α-hydroxyglutarate is a cell-permeable derivative of 2-HG.
References
1. Rzem, R., Veiga-da-Cunha, M., No?l, G., et al. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria Proc. Natl. Acad. Sci. USA 101(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 aciduria Clin. 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 aciduria Am. J. Hum. Genet. 76(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-hydroxyglutarate Cancer Cell 17(3),225-234(2010).
5. Yang, H., Ye, D., Guan, K.L., et al. IDH1 and IDH2 mutations in tumorigenesis: Mechanistic insights and clinical perspectives Clin. 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 dioxygenases Cancer Cell 19(1),17-30(2011).
7. Chowdhury, R., Yeoh, K.K., Tian, Y.M., et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases EMBO Rep. 12(5),463-469(2011).
