About Fumarate Hydratase:
Fumarase (fumarate hydratase) is an enzyme occurring in the human body, and indeed in all aerobic organisms.
The function of fumarase is to catalyze the hydration/dehydration process of fumarate to malate. This is a reversible process. Fumarase can be mitochondrial or cytosolic. The mitochondrial version is instrumental in the functioning of the Krebs Cycle (also known as the Citric Acid Cycle). Cytosolic fumarase helps to metabolize amino acids.
As well as the citric acid cycle, Fumarate hydratase is also involved in the reductive citric acid cycle, i.e. CO2 fixation. It also plays a pivotal role in the development of renal cell carcinoma. Research suggests that mutations in the gene responsible for the production of fumarase are associated with the development of leiomyomas in the uterus and skin.
The core of fumarase crystal structures is formed of two occupied dicarboxylate binding sites, according to observations of fumarase C. The two binding sites are referred to as the “active site” and the “B site”. Both can be identified as having areas that are not occupied by a bound ligand. This structure, observed in fumarase crystals, is sometimes called a “free” crystal structure because there is observable conservation of water in the active site. This orientation is not limited to a single fumarase C crystal structure but has been observed in multiple fumarase C crystal structures. Research on the B site of this enzyme has found a shift on His129, which suggests that one of the permanent components of the active site is water. It may also be that an imidazole-imidazolium conversion controls access to the allosteric B site.
In the citric acid cycle, fumarase plays a key transitional role in the production of NADH (Nicotinamide adenine dinucleotide), which is one of the most important metabolic chemicals. In short, fumarase is essential to the production of energy. Fumarase also plays a role within the cytosol of living cells to metabolize byproducts of the urea cycle.
Due to the key function of fumarase in the Krebs cycle, fumarase deficiency and mutations in the FH (i.e. fumarate hydratase) gene responsible for the production of the enzyme can have severe consequences.
Individuals with FH mutations are at high risk of leiomyomatosis and renal cell cancer (which, because they occur together, are often referred to collectively as HLRCC). Renal cell cancer results in tumors in the kidneys: the most common type of kidney cancer found in those afflicted by FH mutations is known as type 2 papillary renal cancer.
Fumarase deficiency typically manifests early in severe symptoms including microcephaly, seizures and hypotonia. While microcephaly is the most common, other kinds of craniofacial dysmorphism are also found, such as hypertelorism or a depressed nasal bridge. A wide range of cerebral malformations have also been found in cases of fumarase deficiency. Some patients suffer muscular atrophy, dystonia and paralyzed upgaze. Fumarase deficiency also shows in large quantities of fumaric acid contained in the urine. There is no effective treatment for fumarase deficiency, but research is ongoing.