Fumarase deficiency (fumarate hydratase deficiency) is a rare TCA cycle disorder causing severe encephalopathy and lactic acidosis in neonates. Heterozygous mutations in fumarase also predispose to uterine leiomyomas, renal cell carcinoma, and cutaneous leiomyomas (Hereditary Leiomyomatosis and Renal Cell Cancer — HLRCC). Accumulated fumarate acts as an oncometabolite by inhibiting which epigenetic enzyme?
- A DNA methyltransferase (DNMT3A), leading to global hypomethylation
- B Prolyl hydroxylase domain proteins (PHDs), stabilizing HIF-1alpha and activating pseudohypoxic gene expression ✓
- C Histone deacetylase (HDAC), leading to aberrant histone acetylation patterns
- D EZH2 (histone H3K27 methyltransferase), causing loss of polycomb repressive complex activity
Explanation
Accumulated fumarate (and also succinate in SDH-deficient tumors) competitively inhibits prolyl hydroxylase domain proteins (PHD1-3) and factor inhibiting HIF (FIH). PHDs normally hydroxylate HIF-1alpha on proline residues, marking it for VHL-mediated ubiquitination and proteasomal degradation. When PHDs are inhibited by fumarate, HIF-1alpha accumulates and dimerizes with HIF-1beta to activate hypoxia-responsive genes (VEGF, GLUT1, glycolytic enzymes) even under normoxic conditions — a 'pseudohypoxia' state. Fumarate also inhibits the TET2 DNA demethylase (an alpha-ketoglutarate-dependent dioxygenase), causing epigenetic dysregulation. The fumarate/succinate/2-HG (2-hydroxyglutarate) concept of oncometabolites is a major cancer biology advance.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.