Fumarate (together with Succinate and Malate) is used in the body’s metabolic pathway that generates cellular energy – the Citric Acid Cycle. This cycle critically supports organ maintenance and neurological function. Fumarate is also a product of the urea cycle. Much like vitamin D, fumaric acid is formed by the body, in the skin, during exposure to sunlight.
Low levels of fumarate can occur if there are low levels of precursors (succinate, tyrosine), if there are nutritional enzyme inhibitions, or if a low-activity enzyme variant is inherited. CoQ10 is a required cofactor for fumarate synthesis from succinate and electron transport chain (ETC) complex II. Fumarate is also generated by the urea cycle and the metabolism of neurotransmitter precursors phenylalanine and tyrosine. Low levels of fumarate may indicate problems with these other pathways.
→ The enzyme that converts succinate into fumarate is a component of ETC complex II and makes ATP energy molecules. The enzyme requires two cofactors, CoQ10, and iron- dependent heme protein. Adult-onset complex II ETC inherited defects are rare and may present with cardiac problems or muscle weakness, incoordination, and possibly seizures.
-- Enzyme function may be inhibited in patients with anemia or iron deficiency. Lead, cadmium, or other toxic metal exposures may disrupt heme synthesis. Inherited heme synthesis defects may also occur.
-- Complex II (succinate dehydrogenase) defects present with elevated lactate (possible elevated succinate, fumarate)
-- Consider supporting ETC function with additional vitamins B2, B3, B5, B12, E, selenium, taurine and melatonin.
→ The phenylalanine/tyrosine metabolic pathway requires nutrient cofactors to produce fumarate. Consider supporting this pathway with vitamins B2, B6, calcium, iron (if deficient), and magnesium.
→ If fumarate is not produced by the urea cycle pathway, arginine levels may also be low. Arginine is a critical regulator of nitric oxide and vascular health. Arginine deficiency may increase orotate levels.
Elevated levels of fumarate occur if there are nutritional enzyme inhibitions of the breakdown pathways, inherited low-activity enzymes (fumarase) are present, if there are high levels of precursors (succinate, tyrosine), or if there are higher levels of its downstream products (malate). Low-activity fumarase variants may increase cancer risks. Fumarase does not require any nutritional cofactors.
→ Fumarase is typically a bi-directional enzyme that allows the interconversion of fumarate and malate. If there is a low-activity variant, the enzyme may have a more directional (one-way) effect. Individuals with a low activity fumarase variant may benefit from a low carbohydrate, higher fat “keto” diet.
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