Fumarate hydratase, mitochondrial (FH) (FH)

Fumarate hydratase (FH) is a critical metabolic enzyme that catalyzes the reversible hydration of fumarate to L-malate within the mitochondrial matrix as part of the tricarboxylic acid (TCA) cycle (UniProt: P07954). It exists as a homotetramer and is essential for cellular energy production and aerobic respiration (PubMed: 21822276). Beyond its metabolic function, FH acts as a tumor suppressor; its inactivation leads to the accumulation of fumarate, which functions as an oncometabolite by competitively inhibiting alpha-ketoglutarate-dependent dioxygenases (PubMed: 21670265). This inhibition results in the stabilization of hypoxia-inducible factors (HIF) and promotes oncogenic signaling, a state often referred to as pseudohypoxia (NIH: GeneReviews). Germline mutations in the FH gene are the underlying cause of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a syndrome characterized by benign smooth muscle tumors and aggressive kidney cancer (PubMed: 11865300). While FH is typically lost in these cancers, it is a focal point for synthetic lethality research, where the metabolic shifts caused by FH deficiency—such as dependence on heme oxygenase 1—are targeted to selectively kill cancer cells (PubMed: 21822276).

Other names

FumaraseFHHLRCCMCLMCUL1

Catalyzes the reversible hydration of fumarate to L-malate (UniProt: P07954). In FH-deficient cancers, the loss of this enzyme is exploited through synthetic lethality, targeting enzymes like heme oxygenase 1 (PubMed: 21822276).