IDH1/IDH2 mutations in gliomas and AML produce 2-hydroxyglutarate (2-HG). How does 2-HG act as an oncometabolite?

• A It activates mTOR signaling directly
• B It competitively inhibits alpha-ketoglutarate-dependent dioxygenases causing epigenetic dysregulation ✓
• C It blocks the urea cycle causing hyperammonemia
• D It increases HIF-1alpha stability by inhibiting PHD enzymes only

Explanation

Mutant IDH1/IDH2 gains neomorphic activity, reducing alpha-ketoglutarate (αKG) to 2-HG rather than performing normal isocitrate-to-αKG conversion. 2-HG structurally mimics αKG and competitively inhibits αKG-dependent dioxygenases, including TET enzymes (5-methylcytosine demethylation), histone demethylases (KDMs/JMJDs), and prolyl hydroxylases. This blocks epigenetic reprogramming necessary for differentiation, establishing a hypermethylator phenotype (CpG island methylator phenotype, CIMP). Option D is partially correct but incomplete — PHD inhibition is one consequence.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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