IDH1 (R132H mutant; human, recombinant)

Isocitrate dehydrogenases (IDHs) are NAD⁺ and NADP⁺-dependent enzymes that catalyze the third step of the tricarboxylic acid cycle. IDHs catalyze oxidative decarboxylation of isocitrate producing α-ketoglutarate (α-KG) and carbon dioxide. IDH1 (cytosolic) and IDH2 (mitochondrial) are NADP⁺-dependent enzymes that catalyze reversible reactions. The IDH3 isoform, a NAD⁺-dependent multisubunit enzyme, is irreversible and allosterically regulated by a variety of positive (calcium, ADP, and citrate) and negative (ATP, NADH, and NADPH) effectors.¹ IDH1 and IDH2 are mutated in >70% of lower grade gliomas.² The most common IDH mutation, Arg132His, imparts new gain of function catalytic activity leading to the NADPH-dependent conversion of α-KG to 2-hydroxyglutarate.^3,4 Astrocytes expressing IDH1 R132H mutant have been shown to produce markedly increased levels of the R-2-hydroxyglutarate enantiomer, leading to transformation of cells through the HIF prolyl 4-hydroxylase, EGLN.⁵

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1. Raimundo, N., Baysal, B.E., and Shadel, G.S. Revisiting the TCA cycle: Signaling to tumor formation. Trends Mol. Med. 17(11), 641-649 (2011).

2. Turcan, S., Rohle, D., Goenka, A., et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483(7390), 479-483 (2012).

3. Reitman, Z.J., and Yan, H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: Alterations at a crossroads of cellular metabolism. J. Natl. Cancer Inst. 102(13), 932-941 (2010).

4. Dang, L., White, D.W., Gross, S., et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462(7274), 739-744 (2009).

5. Koivunen, P., Lee, S., Duncan, C.G., et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483(7390), 484-488 (2012).