Orotic acid is a naturally occurring organic compound, classified as a pyrimidinedione and a carboxylic acid. Found within the human body, it serves as a precursor molecule for pyrimidines, which are fundamental components of DNA and RNA.
Its Role in Metabolism
Orotic acid plays a central role as an intermediate in the de novo pyrimidine synthesis pathway, where pyrimidine nucleotides are built from simpler compounds. This pathway is essential for creating DNA and RNA. Orotic acid is formed from dihydroorotate through the action of the enzyme dihydroorotate dehydrogenase.
Following its formation, orotic acid combines with phosphoribosyl pyrophosphate (PRPP) to create orotidine-5′-monophosphate (OMP). This is followed by further conversions to produce uridine monophosphate (UMP), a direct precursor to other pyrimidine nucleotides.
Orotic acid’s connection to the urea cycle is important in certain metabolic disorders. The urea cycle removes ammonia from the body. If excess ammonia or a defect in urea cycle enzymes occurs, carbamoyl phosphate can accumulate. This excess carbamoyl phosphate can then enter the pyrimidine synthesis pathway, leading to elevated production and excretion of orotic acid.
Orotic Acid and Health Implications
Abnormal levels of orotic acid can indicate underlying health conditions, particularly genetic and metabolic disorders. The most recognized condition is orotic aciduria, a rare genetic disorder characterized by excessive excretion of orotic acid in the urine. This condition results from a deficiency in uridine monophosphate synthase (UMPS), an enzyme involved in the later steps of pyrimidine synthesis.
Hereditary orotic aciduria is an autosomal recessive disorder that presents in infancy or early childhood. Symptoms can include megaloblastic anemia, a type of anemia where red blood cells are abnormally large, and developmental delays. The anemia in orotic aciduria is resistant to conventional treatments like folic acid or vitamin B12 supplementation. Diagnosis involves detecting high levels of orotic acid in the urine, along with low UMPS activity.
Orotic aciduria can also occur as a secondary condition due to defects in the urea cycle, such as ornithine transcarbamylase (OTC) deficiency. In these cases, increased orotic acid results from the diversion of carbamoyl phosphate to pyrimidine synthesis. Distinguishing between hereditary orotic aciduria and urea cycle disorders involves assessing blood ammonia levels; high ammonia levels with elevated orotic acid suggest a urea cycle defect, whereas hereditary orotic aciduria does not affect the urea cycle or cause hyperammonemia. Elevated orotic acid levels can also be observed in liver conditions or as a side effect of some medications, including anti-cancer drugs like allopurinol and 6-azauridine.
Orotic Acid in Supplements and History
Historically, orotic acid was once classified as “Vitamin B13,” though it is no longer recognized as a true vitamin because the human body can synthesize it. Despite this reclassification, orotic acid has found a place in nutritional supplements, often in the form of “orotate” salts. These include compounds like magnesium orotate, potassium orotate, and lithium orotate.
The orotate form of minerals is believed to enhance their absorption and cellular delivery. For instance, magnesium orotate is suggested to have higher bioavailability compared to other magnesium forms, potentially allowing for better utilization within cells. Proponents of orotate supplements suggest benefits such as improved cellular energy production, enhanced mineral transport across cell membranes, and support for cardiovascular health. Some research indicates that magnesium orotate may improve exercise tolerance and could have beneficial effects on the myocardium under stress conditions. However, scientific evidence supporting many of these purported benefits is still developing or limited, and the United States Food and Drug Administration has not set a recommended daily allowance for orotic acid.