Citric acid, cis-aconitic acid, and isocitric acid are the first three metabolites in the Krebs Citric Acid energy production cycle, which operates in the mitochondria of your cells.
Citrate, cis-Aconitate (and Isocitrate) are involved in both energy production and removal of toxic ammonia.
High levels can indicate ammonia toxicity. Chronic loss of these valuable compounds can contribute to loss of organ reserve and disturbances in neurological function. If they are low they can indicate a need for essential amino acids, especially arginine.
- Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid
metabolism in bipolar disorder [https://dash.harvard.edu/bitstream/handle/1/26860076/4832124.pdf?sequence=1]
- Might be due to low or high pyruvic acid or low acetyCoA (from fatty acid oxidation)
- 2° to subnormal upstream metabolites.
If Isocitric Acid is measured to be subnormal:
This may be due to deficient or low-normal levels of its precursors, cis-aconitate or citrate. It may also be due to depleted alpha-ketoglutarate, which it forms in the citric acid cycle.
### check for low alpha-ketoglutarate
The same enzyme, aconitase, forms cis-aconitic acid and isocitric acid, and requires reduced cysteine or glutathione and ferrous iron (Fe+2). Oxidant stress can inhibit it, as can arsenic, mercury or antimony. Fluoride that becomes fluorocitrate can strongly inhibit aconitase and impair formation of isocitrate.
Impaired metabolism due to toxic metals (Fl, Hg, As, Sb) OR low cofactors (Fe, GSH— depleted in oxidative stress); OR high amounts of dietary citric acid; OR metabolic acidosis (if mildly increased cis-aconitic acid but markedly increased citric acid). High Citrate and Cis-aconitate can indicate arginine insufficiency for ammonia clearance through the Urea Cycle Consider supplementing with arginine Rule out toxic metals; glutathione, N-acetylcysteine, Mg, or L-glutamine; consider antioxidants; rule out pancreatic insufficiency (can lead to metabolic acidosis from deficient bicarbonate).
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