Fumarate hydratase (FH)

Fumarate hydratase (FH), also commonly known as fumarase, is a ubiquitous mitochondrial enzyme central to the tricarboxylic acid (TCA) cycle, catalyzing the reversible hydration of fumarate to L-malate and supporting core cellular respiration in nearly all eukaryotes[2][3][4][5][6][7]. In addition to its mitochondrial function, FH exists in a cytosolic form where it contributes to the DNA damage response by modulating DNA repair through local generation of fumarate, which affects chromatin modification and repair pathway choice[1][5][6]. Germline or somatic mutations in the FH gene are associated with hereditary leiomyomatosis and renal cell cancer (HLRCC), and bi-allelic deficiency leads to severe congenital fumarase deficiency, often resulting in fatal neurological impairment[4][5][6]. FH is recognized as a tumor suppressor, as its inactivation drives oncogenesis via metabolic and genetic stress pathways[5][6]. There are no direct approved therapeutics targeting FH, but its loss or dysfunction serves as a key cancer biomarker and as a mechanistic hypothesis for emerging therapeutic strategies[4][5].

Other names

FumaraseFumarase hydrataseFumarate hydrataseFH

Enzyme inhibition (research setting: small molecules/peptides can inhibit FH, leading to fumarate accumulation) Restoration or mimicry (supplementing fumarate rescues non-metabolic DNA repair functions in models)