IDH1/IDH2 mutations found in gliomas and AML produce the oncometabolite 2-hydroxyglutarate (2-HG), which causes cancer by:

• A Activating mTOR through allosteric binding to Raptor
• B Inhibiting Complex II of the electron transport chain
• C Inhibiting alpha-ketoglutarate-dependent dioxygenases, causing hypermethylation of DNA and histones ✓
• D Competitively inhibiting HIF-1alpha hydroxylation, stabilising HIF-1alpha

Explanation

Mutant IDH1/2 reduces alpha-ketoglutarate (αKG) to the oncometabolite (R)-2-hydroxyglutarate; 2-HG competitively inhibits αKG-dependent dioxygenases including TET2 (DNA demethylase) and KDM histone demethylases, producing a CpG island methylator phenotype (CIMP) with widespread epigenetic silencing of tumour suppressor genes. mTOR, Complex II, and HIF hydroxylation are not the primary mechanisms.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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