IDH1 and IDH2 mutations in gliomas and AML produce a neomorphic enzyme that generates 2-hydroxyglutarate (2-HG) instead of alpha-ketoglutarate. 2-HG causes epigenetic dysregulation by acting as a competitive inhibitor of which class of enzymes?

• A Histone acetyltransferases (HATs)
• B Alpha-ketoglutarate–dependent dioxygenases, including TET methylcytosine hydroxylases and histone demethylases (KDMs) ✓
• C DNA methyltransferases (DNMTs) responsible for de novo methylation
• D PARP enzymes responsible for DNA repair

Explanation

2-Hydroxyglutarate is structurally similar to alpha-ketoglutarate (2-oxoglutarate) and competitively inhibits all 2-OG–dependent dioxygenases. Key targets are TET1/2 (which hydroxylate 5-methylcytosine en route to demethylation) and KDM histone demethylases. Inhibition of TETs causes hypermethylation of CpG islands at tumour suppressor loci (CpG island methylator phenotype, CIMP). KDM inhibition causes histone hypermethylation, resulting in broad epigenetic reprogramming and a differentiation block. HATs use acetyl-CoA, not 2-OG, and are not inhibited by 2-HG. DNMTs add methyl groups using SAM; they are not 2-OG dependent. PARP uses NAD+.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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