Regulation of TET enzymatic activity by metabolites. Metabolic pathways that alter levels of αKG and 2HG. The TET cosubstrate αKG, a TCA cycle intermediate, is produced from isocitrate by the cytoplasmic and mitochondrial isocitrate dehydrogenases IDH1 and IDH2, respectively (left). 2HG, a metabolite structurally similar to αKG, inhibits TET activity (middle). 2HG has 2 stereoisomers, L-2HG, also known as S-2HG (top), and D-2HG, also known as R-2HG (bottom), which are converted back to αKG by L-2-hydroxyglutarate dehydrogenase (L2HGDH) and D-2-hydroxyglutarate dehydrogenase (D2HGDH), respectively. GOF IDH mutations found in glioma, AML, and AITL can convert αKG into D-2HG, the prototype oncometabolite, a less potent inhibitor of TETs and other dioxygenases compared with L-2HG. Endogenous enzymes, such as phosphoglycerate dehydrogenase (PHGDH), an enzyme frequently amplified in breast cancers and melanoma, can also produce D-2HG, although it is not clear whether physiologically relevant concentrations of the metabolite are achieved. The more potent TET inhibitor L-2HG is generated by endogenous enzymes lactate dehydrogenase A (LDHA) and malate dehydrogenases 1 and 2 (MDH1/2). The level of αKG critically affects the activity of TET and other dioxygenases. The enzyme branched-chain amino acid (BCAA) transaminase 1 (BCAT1) reversibly transfers the amino group from the BCAAs leucine, isoleucine, and valine to αKG to yield branched-chain α-keto acids (BCKAs) and glutamate (right). The high levels of BCAT1 found in numerous cancers result in decreased levels of αKG, thus interfering with αKG-dependent enzymes, including TET proteins.