fumarase

Fumarase, also known as fumarate hydratase (FH), is a metabolic enzyme that catalyzes the reversible hydration of fumarate to L-malate in the citric acid cycle. In many organisms it is localized in mitochondria, and in higher eukaryotes a cytosolic form is also present, produced by alternative translation initiation and targeting signals.

Structurally, fumarase belongs to the class II family of fumarases and typically functions as a homotetramer. Each subunit participates in forming the active site, which coordinates a divalent metal ion such as magnesium or manganese required for catalysis. The reaction proceeds via a water-addition mechanism that converts fumarate to malate and can proceed in either direction depending on cellular conditions.

In humans, fumarase is encoded by the FH gene. The enzyme operates primarily in mitochondria as part of the tricarboxylic acid cycle, but a cytosolic pool participates in other metabolic pathways and cellular processes. The dual localization reflects distinct roles in metabolism and cellular signaling.

Clinical significance is notable. Biallelic mutations in FH cause fumarase deficiency, a rare autosomal recessive metabolic disorder characterized by severe intellectual disability, hypotonia, seizures, and brain malformations. Heterozygous germline FH mutations predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC), a syndrome featuring cutaneous and uterine leiomyomas and an increased risk of aggressive renal cell carcinoma. Tumor development is associated with accumulation of fumarate and altered cellular signaling, including pseudohypoxic stabilization of hypoxia-inducible factors.

Fumarase is thus a key enzyme linking core energy metabolism to broader cellular processes and disease, with roles ranging from mitochondrial metabolism to tumor suppression.