Malic

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:

Diet

- Excessive consumption of fruits and vegetables

- Food additives

- Magnesium malate supplements

Malate aspartate shuttle dysfunction

Medical disorders

- Inborn errors of metabolism (disorders are usually diagnosed in infancy)

- Kidney problems (uremia)

Pharmaceutical lithium

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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.

• Individuals with low activity fumarase variants may benefit from a low carbohydrate, higher fat keto diet.

→  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.

• Consider supporting the malate-aspartate shuttle with vitamins B3, B6, and calcium. Shuttle dysfunction may increase malate levels and decrease alpha-ketoglutarate. Liver synthesis of aspartate is B6-dependent.
• Problems in the urea cycle may present with high levels of alpha-ketoisovalerate, alpha- ketoisocaproate, alpha-keto-beta-methylvalerate, beta-hydroxyisovalerate, and orotate.
• Oxaloacetate (not measured) interconverts with malate; the enzyme for this conversion is vitamin B3-dependent. Low oxaloacetate levels may inhibit gluconeogenesis and decrease pyruvate.