Category: biosynthesis
De novo pyrimidine synthesis: carbamoyl-P (CPS2, cytosolic; distinct from urea-cycle CPS1) → orotate → UMP → UTP/CTP. DHODH (dihydroorotate dehydrogenase, mitochondrial inner membrane, FMN cofactor) is the key drug target — LEFLUNOMIDE inhibits DHODH for rheumatoid arthritis (immunosuppression via T-cell pyrimidine starvation). 5-FU is a thymidylate synthase inhibitor (TS converts dUMP → dTMP using methylene-THF — see folate_one_carbon) — chemotherapy + topical for actinic keratosis. Capecitabine is a 5-FU prodrug activated preferentially in tumor cells by thymidine phosphorylase. Salvage path: free pyrimidine bases + nucleosides recycled via thymidine kinase (also acyclovir activation site) + uridine kinase.