Fumarate hydratase (FH), also known as fumarase, is an enzyme found within human cells. It facilitates specific biochemical reactions, helping cells process and utilize molecules. This enzyme exists in two main forms: a mitochondrial isoform and a cytosolic isoform. The mitochondrial form, encoded by the FH gene, is primarily involved in energy production and is fundamental for normal cellular processes.
The Essential Role in Metabolism
Fumarate hydratase performs a specific function within the Krebs cycle, also known as the citric acid cycle or TCA cycle, which takes place in the mitochondria. This cycle is a central metabolic pathway responsible for generating cellular energy. The enzyme catalyzes the reversible hydration of fumarate to L-malate, adding a water molecule to fumarate and converting it into malate, and vice versa.
This conversion is a step in cellular respiration, which ultimately leads to the generation of adenosine triphosphate (ATP). ATP is the primary energy currency of the cell, powering various cellular activities. Fumarate hydratase’s involvement in this reaction contributes to the production of essential molecules like NADH and FADH2, which are then used in the electron transport chain to create ATP.
Consequences of Impaired Fumarate Hydratase Activity
When fumarate hydratase activity is deficient, fumarate accumulates within cells. This disrupts the normal flow of the Krebs cycle. Elevated fumarate levels can then inhibit other enzymes.
Fumarate accumulation leads to a state known as pseudohypoxia. This condition mimics low oxygen levels within the cell, even when oxygen is plentiful. Fumarate inhibits prolyl hydroxylases, enzymes that normally tag hypoxia-inducible factor (HIF) for degradation. When these hydroxylases are inhibited, HIF-1α and HIF-2α proteins stabilize and accumulate, activating genes that typically respond to low oxygen conditions.
This altered cellular metabolism and gene expression can disrupt cellular processes. The sustained activation of HIF target genes, such as those involved in glycolysis, can shift the cell’s metabolic profile towards aerobic glycolysis. These widespread changes contribute to an environment that can promote abnormal cell growth.
The Link to Specific Hereditary Conditions
Mutations in the FH gene, which codes for fumarate hydratase, are linked to specific human genetic conditions. The most recognized is Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), an autosomal-dominant syndrome. This means inheriting one altered copy of the FH gene from a parent puts a person at risk.
HLRCC is characterized by clinical manifestations. Individuals often develop cutaneous leiomyomas, which are benign smooth muscle tumors appearing as firm, reddish papules or nodules on the skin. Women with HLRCC frequently experience multiple, symptomatic uterine leiomyomas, also known as uterine fibroids.
The most serious manifestation of HLRCC is an increased risk of aggressive renal cell carcinoma, a type of kidney cancer. This kidney cancer can progress and metastasize even when tumors are small. Due to its aggressive nature, active surveillance is not recommended; surgical intervention is often advised. Early diagnosis through clinical evaluation, imaging, and genetic testing is important for individuals and families affected by FH deficiency. Annual abdominal imaging, such as MRI, starting from around eight years of age, is recommended for at-risk family members who test positive for the familial FH mutation to detect renal tumors early.