Pyrimidine biosynthesis occurs both in the body and through organic synthesis.

''De novo'' biosynthesis of pyrimidine

''De Novo'' biosynthesis of a

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...

is catalyzed by three gene products CAD, DHODH and UMPS. The first three enzymes of the process are all coded by the same gene in CAD which consists of

carbamoyl phosphate synthetase II Carbamoyl phosphate synthetase (glutamine-hydrolysing) () is an enzyme that catalyzes the reactions that produce carbamoyl phosphate in the cytosol (as opposed to type I, which functions in the mitochondria). Its systemic name is ''hydrogen-carbon ...

, aspartate carbamoyltransferase and dihydroorotase. Dihydroorotate dehydrogenase (DHODH) unlike CAD and UMPS is a mono-functional enzyme and is localized in the mitochondria. UMPS is a bifunctional enzyme consisting of orotate phosphoribosyltransferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC). Both, CAD and UMPS are localized around the mitochondria, in the cytosol. In Fungi, a similar protein exists but lacks the dihydroorotase function: another protein catalyzes the second step. In other organisms ( Bacteria,

Archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...

and the other

Eukaryota Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

), the first three steps are done by three different enzymes.

Pyrimidine catabolism

Pyrimidines are ultimately catabolized (degraded) to CO₂, H₂O, and urea. Cytosine can be broken down to uracil, which can be further broken down to N-carbamoyl-β-alanine, and then to beta-alanine, CO₂, and ammonia by

beta-ureidopropionase In enzymology, a beta-ureidopropionase () is an enzyme that catalyzes the chemical reaction :N-carbamoyl-beta-alanine + H2O \rightleftharpoons beta-alanine + CO2 + NH3 Thus, the two substrates of this enzyme are N-carbamoyl-beta-alanine and H ...

. Thymine is broken down into

β-aminoisobutyrate 3-Aminoisobutyric acid (also known as β-aminoisobutyric acid or BAIBA) is a product formed by the catabolism of thymine. During exercise, the increase of PGC-1α protein triggers the secretion of BAIBA from exercising muscles to blood (concentr ...

which can be further broken down into intermediates eventually leading into the citric acid cycle.

acts as a rough indicator for rate of DNA turnover.

Regulations of pyrimidine nucleotide biosynthesis

Through negative feedback inhibition, the end-products UTP ''and'' UDP prevent the enzyme CAD from catalyzing the reaction in animals. Conversely,

PRPP Phosphoribosyl pyrophosphate (PRPP) is a pentose phosphate. It is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, as well as in pyrimidine nucleotide formation. Hence it is a building block for DNA ...

and

ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...

act as positive effectors that enhance the enzyme's activity.

Pharmacotherapy

Modulating the pyrimidine metabolism pharmacologically has therapeutical uses, and could implement in cancer treatment. ''Pyrimidine synthesis inhibitors'' are used in active moderate to severe rheumatoid arthritis and psoriatic arthritis, as well as in

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

. Examples include Leflunomide and Teriflunomide (the active metabolite of leflunomide).

Prebiotic synthesis of pyrimidine nucleotides

In order to understand how life arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausible prebiotic conditions. The RNA world hypothesis holds that in the primordial soup there existed free-floating pyrimidine and purine ribonucleotides, the fundamental molecules that combine in series to form

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

. Complex molecules such as RNA must have emerged from relatively small molecules whose reactivity was governed by physico-chemical processes. RNA is composed of

and purine nucleotides, both of which are necessary for reliable information transfer, and thus natural selection and Darwinian evolution. Becker et al. showed how pyrimidine nucleosides can be synthesized from small molecules and ribose, driven solely by wet-dry cycles.Becker S, Feldmann J, Wiedemann S, Okamura H, Schneider C, Iwan K, Crisp A, Rossa M, Amatov T, Carell T. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science. 2019 Oct 4;366(6461):76-82. doi: 10.1126/science.aax2747. PMID 31604305

References

External links

Overview
at Queen Mary, University of London {{Purinergics Pyrimidines Metabolism