2-Hydroxyglutarate (2-HG) is an oncometabolite produced by gain-of-function mutations in IDH1/IDH2. Which PRIMARY mechanism drives tumorigenesis?
- A 2-HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, causing DNA and histone hypermethylation (CpG island methylator phenotype) ✓
- B 2-HG directly activates oncogenic RAS by preventing GTP hydrolysis
- C 2-HG inhibits Complex I of the electron transport chain, increasing ROS
- D 2-HG activates mTORC1 by supplying carbon for anapleurosis
Correct answer: A. 2-HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, causing DNA and histone hypermethylation (CpG island methylator phenotype)
Explanation
Normal IDH1/IDH2 convert isocitrate to alpha-ketoglutarate (α-KG). Oncogenic IDH mutations produce a neomorphic enzyme that reduces α-KG to 2-hydroxyglutarate (2-HG). 2-HG structurally resembles α-KG and competitively inhibits a family of α-KG-dependent dioxygenases including TET methylcytosine dioxygenases and histone demethylases (KDMs), resulting in genome-wide DNA and histone hypermethylation — the CpG island methylator phenotype (CIMP) — promoting transformation. This occurs in gliomas, AML, and cholangiocarcinoma.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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