Pyrimidine metabolism


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

''De novo'' biosynthesis of pyrimidine

De Novo biosynthesis of a pyrimidine is catalyzed by 3 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, aspartate carbamoyltransferase and dihydroorotase. Dihydroorotate dehydrogenase unlike CAD and UMPS is a mono-functional enzyme and is localized in the mitochondria. UMPS is a bifunctional enzyme consisting of orotate phosphoribosyltransferase and orotidine monophosphate decarboxylase. 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, the first three steps are done by three different enzymes.

Pyrimidine catabolism

Pyrimidines are ultimately catabolized 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.

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

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.