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
There is no clinical significance to low levels of urinary orotic acid.
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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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% Omega-3s, % Omega-6s, % Omega-9s, % Saturated Fats, 1-Methylhistidine, 3-Hydroxyisovaleric Acid, 3-Hydroxyphenylacetic Acid, 3-Hydroxypropionic Acid, 3-Methyl-4-OH-phenylglycol, 3-Methylhistidine, 4-Hydroxyphenylacetic Acid, 5-OH-indoleacetic Acid, 8-OHdG (urine), a-Amino-N-butyric Acid, a-Aminoadipic Acid, a-Hydroxybutyric Acid, a-Hydroxyisobutyric Acid (from MTBE), a-Keto-b-Methylvaleric Acid, a-Ketoadipic Acid, a-Ketoglutaric Acid, a-Ketoisocaproic Acid, a-Ketoisovaleric Acid, a-Ketophenylacetic Acid (from Styrene), a-Linolenic (ALA) 18:3 n3, AA / EPA (20:4 n6 / 20:5 n3), Adipic Acid, Alanine, Aluminum, Anserine (dipeptide), Antimony, Arachidic C20:0, Arachidonic (AA) 20:4 n6, Arginine, Arsenic, Asparagine, Aspartic Acid, b-Alanine, b-Aminoisobutyric Acid, b-OH-b-Methylglutaric Acid, b-OH-Butyric Acid, Barium, Behenic C22:0, Benzoic Acid, Bismuth, Cadmium, Calcium, Carnosine (dipeptide), Cesium, Chromium, cis-Aconitic Acid, Citramalic Acid, Citric Acid, Citrulline, Cobalt, Copper, Creatinine, Creatinine Concentration (Amino Acids FMV), Cystathionine, Cysteine, Cystine, D-Arabinitol, Dihomo-g-linolenic (DGLA) 20:3 n6, Dihydroxyphenylpropionic Acid (DHPPA), Docosahexaenoic (DHA) 22:6 n3, Docosapentaenoic (DPA) 22:5 n3, Docosatetraenoic (DTA) 22:4 n6, Eicosadienoic 20:2 n6, Eicosapentaenoic (EPA) 20:5 n3, Elaidic 18:1 n9t, Ethanolamine, Formiminoglutamic Acid (FIGlu), g-Aminobutyric Acid, g-Linolenic (GLA) 18:3 n6, Gadolinium, Gallium, Glutamic Acid, Glutamine, Glutaric Acid, Glyceric Acid, Glycine, Glycolic Acid, Hippuric Acid, Histidine, Homovanillic Acid, Indoleacetic Acid, Iron, Isocitric Acid, Isoleucine, Isovalerylglycine, Kynurenic / Quinolinic Ratio, Kynurenic Acid, Lactic Acid, Lead, Leucine, Lignoceric C24:0, Linoleic (LA) 18:2 n6, Linoleic / DGLA (18:2 n6 / 20:3 n6), Lipid Peroxides (urine), Lithium, Lysine, Magnesium, Malic Acid, Manganese, Margaric C17:0, Mercury, Methionine, Methylmalonic Acid, Molybdenum, Nervonic 24:1 n9, Nickel, Niobium, Oleic 18:1 n9, Omega-3 Index, Omega-6s /Omega-3s, Ornithine, Orotic Acid, Oxalic Acid, Palmitic C16:0, Palmitoleic 16:1 n7, Pentadecanoic C15:0, Phenylacetic Acid, Phenylalanine, Phosphoethanolamine, Phosphoserine, Platinum, Potassium, Proline, Pyroglutamic Acid, Pyruvic Acid, Quinolinic Acid, Rubidium, Sarcosine, Selenium, Serine, Stearic C18:0, Strontium, Suberic Acid, Succinic Acid, Sulfur, Tartaric Acid, Taurine, Thallium, Thorium, Threonine, Tin, Tricosanoic C23:0, Tryptophan, Tungsten, Tyrosine, Uranium, Urea, Urine Creatinine, Vaccenic 18:1 n7, Valine, Vanadium, Vanilmandelic Acid, Xanthurenic Acid, Zinc
