Succinate dehydrogenase (SDH) subunit B mutation in hereditary paraganglioma-pheochromocytoma syndrome leads to accumulation of succinate. Succinate is classified as an oncometabolite because it:

• A Stimulates glycolysis by feedback activation of phosphofructokinase
• B Inhibits alpha-ketoglutarate-dependent dioxygenases including TET methylcytosine dioxygenases and PHD enzymes ✓
• C Directly activates HIF-1α transcription in the nucleus
• D Promotes glutamine anaplerosis by activating glutaminase

Explanation

Accumulated succinate (and similarly fumarate in FH mutations, and 2-hydroxyglutarate in IDH1/2 mutations) inhibits alpha-ketoglutarate (αKG)-dependent dioxygenases by competitive inhibition using the structurally similar αKG cofactor binding site. TET enzymes (DNA demethylation) and JMJD histone demethylases are inhibited, causing global hypermethylation and epigenetic reprogramming (CpG island methylator phenotype). PHD (prolyl hydroxylase domain) enzyme inhibition stabilises HIF-1α by preventing its prolyl hydroxylation and subsequent VHL-mediated proteasomal degradation. This is the indirect mechanism of HIF-1α activation, not direct nuclear activation. Succinate does not activate PFK or glutaminase directly.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.