Pyrimidine de novo synthesis + salvage

Category: biosynthesis

Overview

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.

Organ Systems

Pathway Steps

  1. glutamine → carbamoyl-phosphate — via CPS2 (cytosolic; distinct from CPS1 urea cycle). Cytosolic CPS II starts pyrimidine synthesis from glutamine — distinct from mitochondrial CPS1 of the urea cycle (which uses ammonia and needs NAG). CPS II is part of the multifunctional CAD enzyme and is the committed step (ATP-activated, UTP-inhibited).
  2. carbamoyl-phosphate → orotate — via multi-step; DHODH (dihydroorotate dehydrogenase) — LEFLUNOMIDE TARGET. Unlike purines, the pyrimidine ring is built first and only then joined to ribose. Dihydroorotate dehydrogenase (DHODH) is the sole mitochondrial, membrane-bound step (coupled to the respiratory chain) and the target of leflunomide/teriflunomide.
  3. orotate → ump — via UMP synthase (orotate phosphoribosyltransferase + OMP decarboxylase). UMP synthase is bifunctional (orotate phosphoribosyltransferase + OMP decarboxylase) and joins the ring to PRPP-derived ribose to form the first complete pyrimidine nucleotide; its deficiency causes hereditary orotic aciduria.
  4. ump → utp — via kinase phosphorylation; then CTP synthase → CTP. UMP is phosphorylated to UDP/UTP, then CTP synthase aminates UTP to CTP using glutamine. Ribonucleotide reductase makes the deoxy forms for DNA, and thymidylate synthase makes dTMP (the 5-fluorouracil target), a folate-dependent step.

Known Modulators

References