Orotic Acid is an organic acid which serves as an intermediate in nucleotide synthesis and is linked to arginine metabolism as a urea cycle marker for nitrogen balance.
It is formed from aspartic acid and carbamoyl phosphate. Carbamoyl phosphate plays an important role in the body because it brings nitrogen into the urea cycle for detoxification and disposal. Carbamoyl phosphate enters the urea cycle to react with ornithine to form citrulline. When ammonia levels significantly increase or the liver’s capacity for detoxifying ammonia into urea decreases, carbamoyl phosphate leaves the mitochondria and instead enters the pyrimidine pathway. This stimulates orotic acid biosynthesis and subsequent urinary excretion. Orotic acid can also be found in the diet. The richest dietary sources include cow’s milk and dairy products.
Most urinary orotic acid is synthesized in the body as an intermediate in the nucleotide synthesis. Although it is also linked with abnormalities in arginine metabolism as a urea cycle marker for nitrogen balance, orotic acid plays no direct role in the urea cycle, yet is increased in urea cycle disorders. Hyperammonemia is characteristic of all urea cycle disorders; orotic acid is only elevated in a few.
References:
- Brosnan ME, Brosnan JT. Orotic Acid Excretion and Arginine Metabolism. J Nutr. 2007;137(6):1656S-1661S.
- Nyc JF, Mitchell HK. Synthesis of Orotic Acid from Aspartic Acid. J Am Chem Soc. 1947;69(6):1382-1384.
- Visek WJ. Nitrogen-stimulated orotic acid synthesis and nucleotide imbalance. Cancer Res. 1992;52(7 Suppl):2082s-2084s.
- Löffler M, Carrey EA, Zameitat E. Orotate (orotic acid): An essential and versatile molecule. Nucleosid Nucleot Nucl Acids. 2016;35(10- 12):566-577.
- Visek WJ, Shoemaker JD. Orotic acid, arginine, and hepatotoxicity. J Am Coll Nutr. 1986;5(2):153-166.
- Salerno C, Crifo C. Diagnostic value of urinary orotic acid levels: applicable separation methods. J Chromatog B, AnalTechnol Biomed Life Sci. 2002;781(1-2):57-71.
- Choi Y-J, Yoon Y, Lee K-Y, et al. Orotic Acid Induces Hypertension Associated with Impaired Endothelial Nitric Oxide Synthesis. Toxicol Sci. 2015;144(2):307-317.
- Haggard ME, Lockhart LH. Megaloblastic anemia and orotic aciduria. A hereditary disorder of pyrimidine metabolism responsive to uridine. Am J Dis Children (1960). 1967;113(6):733- 740
- Low orotic acid in the presence of high ammonia indicates magnesium deficiency.
- Low orotic acid together with low urea levels suggests your cells are not burning protein for fuel at a very high rate. This is consistent with elevated branched-chain amino acids (leucine, isoleucine and valine). It also means that you do not have gut bacteria that are producing a lot of ammonia. Check the bacterial dysbiosis markers to see if they’re consistent.
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Elevations of orotic acid are seen in with hereditary deficiencies of urea-cycle enzymes, ammonia overload as seen in high protein diets, and abnormalities in arginine metabolism.
Any hepatotoxin or underlying liver condition can affect ammonia metabolism and increase orotic acid. There are studies that show elevations in orotic acid after drinking alcohol, which then declined with abstinence. Orotic acid excretion is increased by allopurinol and 6-azauridine seemingly related to action of these drugs on pyrimidine synthesis. There are animal studies which show a link between orotic aciduria and hypertension. Orotic acid can induce endothelial dysfunction by contributing to vascular and systemic insulin resistance which impacts nitric oxide production, leading to hypertension. Random case studies also show an association between megaloblastic anemia and orotic aciduria as a result of hereditary defects in pyrimidine synthesis.
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1-Methylhistidine, 1-Methylhistidine (Plasma), 2-,3-, and 4-Methylhippuric acid, 2-Methylhippuric Acid, 2-Methylsuccinic Acid, 3,4-Dihydroxyhydrocinnamic Acid, 3,5-Dihydroxybenzoic Acid, 3-Methylhistidine (Plasma), 3-Phenylpropionylglycine, 4-Hydroxybenzoic Acid, 4-Hydroxyphenylacetic Acid, 4-Hydroxyphenylpyruvic Acid, 5-Hydroxyindoleacetic Acid, 8-Hydroxy-2'-deoxyguanosine, a-Hydroxybutyric Acid, a-Keto-b-methylvaleric Acid, a-Ketobutyric Acid, a-Ketoglutaric Acid, a-Ketoisocaproic Acid, a-Ketoisovaleric Acid, a-Aminoadipic Acid (Plasma), Adipic Acid, Alanine, Alanine (Plasma), Aldosterone, Anserine (Plasma), Anthranilic Acid, Arabinitol, Arginine (Plasma), Arginosuccinic Acid, Arginosuccinic Acid (Plasma), Asparagine (Plasma), Aspartic Acid (Plasma), b-Hydroxybutyric Acid, b-Hydroxyisovaleric Acid, b-Alanine (Plasma), Benzoic Acid, Benzoylform, Branched Chain Alpha-Keto Organic Acids, Carnosine, Carnosine (Plasma), cis-Aconitic Acid, Citric Acid, Citrulline (Plasma), Cortisol, Cortisone, Creatinine, Cystathionine (Plasma), Cystine (Plasma), D-Lactic Acid, Equol, Ethanolamine (Plasma), Ethylmalonic Acid, Formiminoglutamic Acid, Fructose, Fumaric Acid, g-Aminobutyric Acid (Plasma), Glucaric Acid, Glucose, Glutamic Acid (Plasma), Glutamine (Plasma), Glutamine / Glutamate Ratio (Plasma), Glutaric Acid, Glycine (Plasma), Glycylproline (Plasma), Hexanoylglycine, Hippuric Acid, Histidine (Plasma), Homocitrulline (Plasma), Homocystine (Plasma), Homogentisic Acid, Homovanillic Acid, Hydroxykynurenine, Hydroxyproline, Hydroxyproline (Plasma), Indoleacetic Acid, Isocitric Acid, Isoleucine/allo-Isoleucine (Plasma), KT Ratio, KT Ratio (Plasma), Kynurenic Acid, Kynurenine, Kynurenine (Plasma), Lactic Acid, Leucine (Plasma), Lysine (Plasma), Malic Acid, Mandelic Acid, Methionine (Plasma), Methylmalonic Acid, Microalbumin, Ornithine, Ornithine (Plasma), Orotic Acid, Oxalic Acid, pH, Phenylacetic Acid, Phenylalanine (Plasma), Phosphate, Phosphoethanolamine (Plasma), Picolinic Acid, Pimelic Acid, Proline (Plasma), Pyridoxic Acid, Pyroglutamic Acid, Pyruvic Acid, Quercetin, Quinolinic Acid, Sarcosine (Plasma), Sebacic Acid, Serine (Plasma), Suberic Acid, Suberylglycine, Succinic Acid, Sulfocysteine (Plasma), Tartaric Acid, Taurine (Plasma), Threonine (Plasma), Total Branched Chain Amino Acids (Plasma), Tryptophan, Tryptophan (Plasma), Tyrosine, Tyrosine (Plasma), Valine (Plasma), Vannilylmandelic Acid, Xanthurenic Acid
