fumarases

Fumarases, or fumarate hydratases (FH), are enzymes that catalyze the reversible hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle. They play a central role in cellular energy metabolism by processing intermediates of the cycle, with malate subsequently converted to oxaloacetate by malate dehydrogenase.

In most eukaryotes and many bacteria, fumarases belong to class II, which are distinct from the iron-sulfur containing class I enzymes found in some bacteria. Class II fumarases are typically tetramers and require a metal cofactor, often zinc, for their catalytic activity. In humans and other vertebrates, fumarase is primarily a mitochondrial enzyme; a cytosolic pool exists as well, and in humans this cytosolic fraction is associated with nonmetabolic roles such as the cellular response to DNA damage.

Localization and regulation can vary across organisms. In humans, FH is encoded by the FH gene and is imported into mitochondria, where most of the enzyme resides. A portion can be found in the cytosol, and evidence suggests it participates in nuclear processes beyond metabolism.

Genetic and clinical relevance is notable. Mutations in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a syndrome characterized by cutaneous and uterine leiomyomas and an elevated risk of aggressive renal tumors. FH deficiency leads to accumulation of fumarate, which can act as an oncometabolite by inhibiting 2-oxoglutarate–dependent dioxygenases, promoting pseudohypoxia and epigenetic alterations.

Beyond the TCA cycle, fumarases have been implicated in additional cellular processes, including responses to DNA damage, reflecting a broader functional repertoire in metabolism and stress signaling.