Isocitrate dehydrogenase [NADP], mitochondrial (IDH2) R140Q mutant-wild-type heterodimer (IDH2 R140Q/WT)

Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) (UniProt P48735). The R140Q mutation is a common gain-of-function alteration found in approximately 9-13% of patients with acute myeloid leukemia (AML), where the enzyme typically functions as a heterodimer composed of one mutant and one wild-type subunit (PubMed: 28579384). This mutant form acquires a neomorphic activity, converting α-KG into the oncometabolite (R)-2-hydroxyglutarate (2-HG). High levels of 2-HG competitively inhibit α-KG-dependent dioxygenases, such as TET2 and JmjC-family histone demethylases, leading to DNA and histone hypermethylation and a subsequent block in cellular differentiation (PubMed: 23934148). Small-molecule inhibitors like enasidenib (AG-221) specifically target the IDH2 R140Q–wild-type heterodimer by binding to the allosteric site at the dimer interface, which stabilizes the enzyme in an open, inactive conformation (PubChem CID 71748056). This inhibition reduces 2-HG production, restores normal epigenetic signaling, and promotes the differentiation of malignant blasts into mature myeloid cells.

Other names

Mutant IDH2 R140QmIDH2 R140QIsocitrate dehydrogenase 2 R140QIDH2 R140Q heterodimer

Allosteric inhibition of the mutant IDH2 enzyme, which prevents the reduction of alpha-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate, thereby restoring normal cellular differentiation (PubMed: 28579384).