IDH1/IDH2 mutations in glioma and AML result in the production of 2-hydroxyglutarate (2-HG) instead of alpha-ketoglutarate. 2-HG is classified as an oncometabolite because it:
- A Directly activates mTORC1 signalling by mimicking leucine sensing
- B Inhibits the electron transport chain complex I, shifting cells to Warburg metabolism
- C Competitively inhibits alpha-KG-dependent dioxygenases including TET enzymes and histone demethylases, causing epigenetic silencing ✓
- D Acts as an allosteric activator of mutant IDH, creating a feed-forward loop increasing its own production
Explanation
2-Hydroxyglutarate is structurally similar to alpha-ketoglutarate (2-oxoglutarate) and competitively inhibits alpha-KG-dependent dioxygenases. This family of enzymes includes TET1/2/3 methylcytosine dioxygenases (DNA demethylation) and JmjC domain-containing histone lysine demethylases (KDMs). Inhibition of TET enzymes causes CpG island hypermethylation and transcriptional silencing of tumour suppressor genes; inhibition of KDMs leads to histone hypermethylation (particularly H3K9me3 and H3K27me3), creating a CpG island methylator phenotype (CIMP). This epigenetic reprogramming blocks differentiation and promotes malignant transformation. mTORC1 activation by 2-HG is not established, and IDH mutations cause loss of normal enzymatic function rather than gain of IDH activation.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.