Pyrimidine metabolism

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

De novo biosynthesis of pyrimidine

carbamoyl phosphate synthetase II[1]carbamoyl phosphateThis is the regulated step in the pyrimidine biosynthesis.
aspartic transcarbamolyase (aspartate carbamoyl transferase)[1]carbamoyl aspartic acid-
dihhydroorotase[1]dihydroorotateDehydration
dihydroorotate dehydrogenase[2] (the only mitochondrial enzyme)orotateDihydroorotate then enters the mitochondria where it is oxidised through removal of hydrogens. This is the only mitochondrial step in nucleotide rings biosynthesis.
orotate phosphoribosyltransferase[3]OMPPRPP is used.
OMP decarboxylase[3]UMPDecarboxylation
uridine-cytidine kinase 2[4]UDPPhosphorylation. ATP is used.
nucleoside diphosphate kinaseUTPPhosphorylation. ATP is used.
CTP synthaseCTPGlutamine and ATP are used.

The first three enzymes are all coded by the same gene in Metazoa (CAD). In Fungi, a similar protein exists but lacks the dihydroorotase function: another protein catalyzes the second step.

In other organisms (Bacteria, Archaea and the other Eukaryota), 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. Thymine is broken down into β-aminoisobutyrate which can be further broken down into intermediates eventually leading into the citric acid cycle.

β-aminoisobutyrate acts as a rough indicator for rate of DNA turnover.[5]

Pharmacotherapy

Modulating the pyrimidine metabolism pharmacologically has therapeutical uses.

Pyrimidine synthesis inhibitors are used in active moderate to severe rheumatoid arthritis and psoriatic arthritis, as well as in multiple sclerosis. Examples include Leflunomide and Teriflunomide.

References

  1. 1 2 3 "Entrez Gene: CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase".
  2. ↑ "Entrez Gene: DHODH dihydroorotate dehydrogenase".
  3. 1 2 "Entrez Gene: UMPS uridine monophosphate synthetase".
  4. ↑ "Entrez Gene: UCK2 uridine-cytidine kinase 2".
  5. ↑ Nielsen, HR; Sjolin, KE; Nyholm, K; Baliga, BS; Wong, R; Borek, E (1974). "Beta-aminoisobutyric acid, a new probe for the metabolism of DNA and RNA in normal and tumorous tissue". Cancer Research. 34 (6): 1381–4. PMID 4363656.
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