What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

Abstract

Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.

Figure 1.

The role of the IDH family of enzymes in the TCA cycle. Shown here are the mitochondrial and cytoplasmic reactions that involve IDH; also shown are the principal mechanisms of entry of glucose and glutamine-derived carbon molecules into the TCA cycle. IDH1 reversibly catalyzes the NADP⁺-dependent decarboxylation of isocitrate to 2OG in the cytoplasm, whereas IDH2 mediates the same reaction in the mitochondria. IDH3 catalyzes the NAD⁺-dependent conversion of isocitrate to 2OG in the mitochondria in a reaction that is irreversible under physiologic conditions. (ACO) Aconitase.

Figure 2.

Reactions catalyzed by wild-type and mutant IDH1 and IDH2. Wild-type IDH1 and IDH2 catalyze a two-step reaction (indicated by blue arrows). The first step involves the oxidation of isocitrate to the unstable intermediate oxalosuccinate. In this reaction, NADP⁺ acts as the hydrogen acceptor and is reduced to NADPH. In the second step of the reaction, the β-carboxyl group is released as carbon dioxide (CO₂), resulting in production of 2OG. Mutant IDH1 and IDH2 catalyze a single-step reaction (indicated by the purple arrow). In this reaction, NADPH is oxidized to NADP⁺, with concomitant reduction of 2OG to (R)-2HG. The mutant enzymes are unable to catalyze the carboxylation of (R)-2HG and therefore cannot generate 2OG. 2OG and 2HG are structurally very similar. They differ only in the replacement of the ketone group in 2OG with a hydroxyl group in 2HG.