Orotic acid () is a pyrimidinedione and a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

. Historically, it was believed to be part of the

vitamin B B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. They are a chemically diverse class of compounds. Dietary supplements containing all eight are referred to as a vita ...

complex and was called vitamin B₁₃, but it is now known that it is not a

vitamin Vitamins are Organic compound, organic molecules (or a set of closely related molecules called vitamer, vitamers) that are essential to an organism in small quantities for proper metabolism, metabolic function. Nutrient#Essential nutrients, ...

. The compound is synthesized in the body via a

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

l enzyme,

dihydroorotate dehydrogenase Dihydroorotate dehydrogenase (DHODH) is an enzyme that in humans is encoded by the ''DHODH'' gene on chromosome 16. The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to ...

or a cytoplasmic enzyme of pyrimidine synthesis pathway. It is sometimes used as a mineral carrier in some

dietary supplements A dietary supplement is a manufactured product intended to supplement a person's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources, or that are synthetic ...

(to increase their

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

), most commonly for lithium orotate.

Synthesis

Dihydroorotate is synthesized to orotic acid by the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

dihydroorotate dehydrogenase, where it later combines with

phosphoribosyl pyrophosphate Phosphoribosyl pyrophosphate (PRPP) is a Sugar phosphates, pentose phosphate. It is a biochemical intermediate in the formation of purine nucleotides via Inosinic acid, inosine-5-monophosphate, as well as in pyrimidine nucleotide formation. Hence ...

(PRPP) to form orotidine-5'-monophosphate (OMP). A distinguishing characteristic of pyrimidine synthesis is that the pyrimidine ring is fully synthesized before being attached to the ribose sugar, whereas purine synthesis happens by building the base directly on the sugar.

Chemistry

Orotic acid is a Bronsted acid and its

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid gives a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as it loses a hydrogen ion in the reve ...

, the orotate

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

, is able to bind to metals. Lithium orotate, for example, has been investigated for use in treating

alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...

, and complexes of

cobalt Cobalt is a chemical element; it has Symbol (chemistry), symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. ...

manganese Manganese is a chemical element; it has Symbol (chemistry), symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese was first isolated in the 1770s. It is a transition m ...

nickel Nickel is a chemical element; it has symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive, but large pieces are slo ...

, and

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

are known. The pentahydrate nickel orotate

coordination complex A coordination complex is a chemical compound consisting of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of chemical bond, bound molecules or ions, that are in turn known as ' ...

converts into a polymeric trihydrate upon heating in water at 100 °C. Crystals of the trihydrate can be obtained by hydrothermal treatment of nickel(II) acetate and orotic acid. When the reactions are run with bidentate nitrogen ligands such as 2,2'- bipyridine present, other solids can be obtained.

Pathology

A buildup of orotic acid can lead to

orotic aciduria Orotic aciduria (AKA hereditary orotic aciduria) is a disease caused by an enzyme deficiency, resulting in a decreased ability to synthesize pyrimidines. It was the first described enzyme deficiency of the ''de novo'' pyrimidine synthesis pathway. ...

and acidemia. It may be a symptom of an increased

ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...

load due to a

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...

, such as a urea cycle disorder. In

ornithine transcarbamylase deficiency Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle, r ...

, an X-linked inherited and the most common urea cycle disorder, excess carbamoyl phosphate is converted into orotic acid. This leads to an increased serum ammonia level, increased serum and urinary orotic acid levels and a decreased serum blood urea nitrogen level. This also leads to an increased urinary orotic acid excretion, because the orotic acid is not being properly utilized and must be eliminated. The hyperammonemia depletes alpha-ketoglutarate leading to the inhibition of the

tricarboxylic acid cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions that release the energy stored in nutrients through acetyl-CoA oxidation. The e ...

(TCA) decreasing

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(ATP) production. Orotic aciduria is a cause of megaloblastic anaemia.

Biochemistry

Orotic acid is a precursor to a RNA base, uracil. The

breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a var ...

of smokers has a higher concentration of orotic acid than that of a non smoking

woman A woman is an adult female human. Before adulthood, a female child or Adolescence, adolescent is referred to as a girl. Typically, women are of the female sex and inherit a pair of X chromosomes, one from each parent, and women with functi ...

. It is reasoned that the smoking causes the pyrimidine biosynthesis process in the mother to be altered thus causing the orotic acid concentration to increase. A modified orotic acid (5-fluoroorotic acid) is toxic to

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...

. The mutant yeasts which are resistant to 5-fluoroorotic acid require a supply of

uracil Uracil () (nucleoside#List of nucleosides and corresponding nucleobases, symbol U or Ura) is one of the four nucleotide bases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via ...

References

External links

* {{DEFAULTSORT:Orotic Acid Pyrimidinediones Enoic acids