IDH1 and IDH2 mutations are found in >70% of low-grade gliomas and secondary glioblastomas. Wild-type IDH catalyses isocitrate → alpha-ketoglutarate (α-KG) in the TCA cycle. Mutant IDH (neomorphic activity) produces an oncometabolite that inhibits alpha-KG-dependent dioxygenases. This oncometabolite is:
- A 2-hydroxyglutarate (2-HG) ✓
- B Succinate
- C Fumarate
- D Citrate
Explanation
Mutant IDH1 (R132H most common) and IDH2 (R172K, R140Q) gain a neomorphic activity: they reduce alpha-ketoglutarate (α-KG) to (R)-2-hydroxyglutarate (2-HG, the D-enantiomer) using NADPH. 2-HG is a competitive inhibitor of α-KG-dependent dioxygenases including TET2 (DNA demethylase), histone demethylases (KDMs), and prolyl hydroxylases. Inhibition of TET2 and KDMs causes a CpG island methylator phenotype (CIMP) and histone hypermethylation, blocking cellular differentiation — an epigenetic mechanism of oncogenesis. IDH1/2 mutations are targetable with ivosidenib (IDH1) and enasidenib (IDH2) in AML. Similarly, SDH and FH mutations cause succinate and fumarate accumulation respectively.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.