Figure 4

TET protein as a linker between metabolism and epigenetic regulation. During the tricarboxylic acid (TCA) cycle, IDH enzymes catalyze the oxidative decarboxylation of isocitrate to generate 2-oxoglutarate (2OG), an essential co-substrate that TET enzymes require to oxidize their substrates. Mutations in the IDH1 gene increase the binding affinity for NADPH relative to isocitrate and NADP⁺; thus, the resulting mutant enzymes acquire neomorphic activity to reduce 2OG to 2-hydroxyglutarate (2HG). Owing to the structural similarity, 2HG can function as a competitive inhibitor of TET enzymes.