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 among Pixorize's visual mnemonics for the USMLE Step 1 and NBME Shelf Exams.