Mutations in this gene have been associated with the development of leiomyomas in the skin and uterus in combination with renal cell carcinoma (HLRCC syndrome).

Class I fumarases are change state or become inactive when subjected to heat or radiation, are sensitive to superoxide anion, are iron (Fe2+) dependent, and are dimeric proteins with each subunit consisting of around 120 kD.

Class II fumarases, found in prokaryotes as well as in eukaryotes, are tetrameric enzymes with subunits of 200 kD that contain three distinct segments of significantly homologous amino acids.

The reaction itself can be monitored in either direction; however, it is the formation of fumarate from S-malate in particular that is less understood due to the high pKa value of the HR atom (Fig.

This led to the conclusion that the formation of S-malate proceeds as E1 elimination - protonation of fumarate to create a carbocation was followed by the addition of a hydroxyl group from H2O.

[9][10][11] The function of fumarase in the citric acid cycle is to facilitate a transition step in the production of energy in the form of NADH.

[12] In the cytosol, the enzyme functions to metabolize fumarate, which is a byproduct of the urea cycle as well as amino acid catabolism.

Studies have revealed that the active site is composed of amino acid residues from three of the four subunits within the tetrameric enzyme.

In the newborn period, findings include severe neurologic abnormalities, poor feeding, failure to thrive, and hypotonia.

Fumarase deficiency is suspected in infants with multiple severe neurologic abnormalities in the absence of an acute metabolic crisis.

These include benign mesenchymal tumors of the uterus, leiomyomatosis and renal cell carcinoma, and fumarase deficiency.