# De Novo Pyrimidine Synthesis

**De Novo Pyrimidine Synthesis** describes the biochemical pathway used to make pyrimidine nucleotides from building blocks in the cell.

Pyrimidine Synthesis begins with **glutamine** and **carbon dioxide**, which combine to form **carbamoyl phosphate**, in a reaction catalyzed by **CPS2**. Carbamoyl phosphate then combines with **aspartate** to form **orotic acid**, through steps that can be inhibited by **leflunomide**. Afterwards, orotic acid reacts with **PRPP** to form **UMP**, in a reaction that is impaired in **orotic aciduria**.

UMP is then phosphorylated to **UDP**, which has two possible fates: it can be converted into the pyrimidine nucleotide, **CTP**, or undergo reduction by ribonucleotide reductase ( **RNR)** to **dUDP**. Notably, RNR can be inhibited by the drug, **hydroxyurea**. dUDP is then dephosphorylated to **dUMP**, which in turn undergoes methylation by **thymidylate synthetase** to form **dTMP**.

Thymidylate synthetase can be blocked by the drug, **5-fluorouracil (5-FU)**, or by its prodrug, **capecitabine**. Thymidylate synthetase also requires the cofactor **N5,N10-methylene-THF**, whose regeneration can be blocked by **DHFR antagonists** such as **pyrimethamine**, **methotrexate**, and **trimethoprim**. The reduction in THF by methotrexate can be reversed by **leukovorin (folinic acid)**, which serves as an alternative source for N5,N10-methylene-THF ( **leukovorin rescue**).

Find De Novo Pyrimidine Synthesis and more [Biochemical Pathways](/content/browse#playlist-4028/index.html) among Pixorize's visual mnemonics for the USMLE Step 1 and NBME Shelf Exams.