Fumaric acid uses the fumarase enzyme to become malic acid. Malate dehydrogenase catalyzes the conversion of malic acid into oxaloacetate. Two forms of this enzyme exist in eukaryotes. One operates within the mitochondria to contribute to the Citric Acid Cycle; the other is in the cytosol where it participates in the malate/ aspartate shuttle. Riboflavin is an important cofactor for this enzyme and overall mitochondrial energy production and cellular function. At the end of each Citric Acid Cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.
- Minarik P, Tomaskova N, Kollarova M, Antalik M. Malate dehydrogenases-structure and function. Gen Physiol Biophys. 2002;21(3):257-266.
- Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chemico-biol Interact. 2006;163(1-2):94-112.
- Kim D CJ, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, Zaslvasky L, et. al. PubChem 2019 update: improved access to chemical data. Nucleic Acids. 2019.
High levels of malic acid can be seen if its dehydrogenation to oxaloacetic acid is reduced from lack of vitamin B3 as NAD. Malic acid also has many food sources, such as vegetables, as well as fruits like apples and pears. It is also an additive and preservative in beverages, throat lozenges, and syrups.
Increased urinary malate levels with:
- Excessive consumption of fruits and vegetables
- Food additives
- Magnesium malate supplements
Malate aspartate shuttle dysfunction
- Inborn errors of metabolism (disorders are usually diagnosed in infancy)
- Kidney problems (uremia)
Elevated levels of malate may occur when there are nutritional enzyme inhibitions of the breakdown pathways, inherited low-activity enzymes are present, if there are high levels of precursors (fumarate), or if there are higher levels of its downstream products.
Levels may be high if there are problems with the malate-aspartate shuttle. Dicarboxylic acids (cis-aconitate, isocitrate, succinate, malate, suberate, and adipate) may be excreted in high amounts due to increased mobilization of fatty acids, beta-oxidation defects, increased gut permeability or fasting.
→ Malate can be broken down into several different compounds. Consider supporting malate metabolism with vitamin B3, magnesium and manganese (if deficient).
→ Fumarate is normally in equilibrium with malate. High malate levels due to low-activity enzyme variants in the enzyme fumarase have been associated with increased cancer risk and catecholamine-producing tumors such as paraganglioma, or pheochromocytoma.
→ The malate-aspartate shuttle helps feed electrons into the electron transport chain so that ATP can be produced. High levels of methylmalonate may inhibit shuttle activity. The shuttle may be inhibited if there are problems in the urea cycle or if there is insufficient dietary protein assimilation or aspartate amino acid synthesis. Liver disorders may impair aspartate synthesis.
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