Figure 2. IDH1/2 mutations lead to increased production of the oncometabolite that alters DNA methylation.

(A) Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) catalyze the conversion of isocitrate to α-ketoglutarate (αKG). αKG, along with Fe(II), is an essential cofactor for TET2 and contributes to the active demethylation of DNA. (B) Mutations in IDH1 and IDH2 alter the affinity of the enzymes for their substrates, leading to conversion of αKG to R-2-hydroxyglutarate (R-2-HG). In addition to αKG depletion, R-2-HG inhibits TET2 and other αKG-dependent enzymes, resulting in DNA hypermethylation. Illustrated by Rachel Davidowitz.