Pyrimidine metabolism

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

De novo biosynthesis of pyrimidine
Steps Enzymes Products
1 carbamoyl phosphate synthetase II[1]carbamoyl phosphateThis is the regulated step in the pyrimidine biosynthesis in animals.
2 aspartic transcarbamolyase (aspartate carbamoyl transferase)[1]carbamoyl aspartic acidThe phosphate group is replaced with Aspartate. This is the regulated step in the pyrimidine biosynthesis in bacteria.
3 dihydroorotase[1]dihydroorotateRing formation and Dehydration.
4 dihydroorotate dehydrogenase[2] (the only mitochondrial enzyme)orotateDihydroorotate then enters the mitochondria where it is oxidized through removal of hydrogens. This is the only mitochondrial step in nucleotide rings biosynthesis.
5 orotate phosphoribosyltransferase[3]OMPPRPP donates a Ribose group.
6 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.

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 (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. [5]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.[6]

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.[7]

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.[8]

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. "Entrez Gene: CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase".
  2. "Entrez Gene: DHODH dihydroorotate dehydrogenase".
  3. "Entrez Gene: UMPS uridine monophosphate synthetase".
  4. "Entrez Gene: UCK2 uridine-cytidine kinase 2".
  5. Chitrakar I, Kim-Holzapfel DM, Zhou W, French JB (March 2017). "Higher order structures in purine and pyrimidine metabolism". Journal of Structural Biology. 197 (3): 354–364. doi:10.1016/j.jsb.2017.01.003. PMID 28115257.
  6. Garavito MF, Narváez-Ortiz HY, Zimmermann BH (May 2015). "Pyrimidine Metabolism: Dynamic and Versatile Pathways in Pathogens and Cellular Development". Journal of Genetics and Genomics = Yi Chuan Xue Bao. 42 (5): 195–205. doi:10.1016/j.jgg.2015.04.004. PMID 26059768.
  7. Nielsen HR, Sjolin KE, Nyholm K, Baliga BS, Wong R, Borek E (June 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.
  8. Jones ME (June 1980). "Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis". Annual Review of Biochemistry. 49 (1): 253–79. doi:10.1146/annurev.bi.49.070180.001345. PMID 6105839.
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