Pyrimidine Metabolism
Pyrimidines (Cytosine, Thymine, and Uracil) are single-ring nitrogenous bases. Unlike purines, the pyrimidine ring is synthesized first, then attached to ribose. They are also salvaged from nucleotide turnover.
De Novo Pyrimidine Synthesis
The ring is built from: Aspartate, Glutamine, CO₂ (no folate needed for ring itself, but THF needed for dTMP).
Key first steps involve a trifunctional enzyme CAD (in animals, including humans):
- Glutamine + CO₂ + ATP → Carbamoyl Phosphate [CPS-II — in cytosol; different from CPS-I in mito for urea cycle] — rate-limiting
- Carbamoyl-P + Aspartate → Carbamoyl Aspartate [ATCase]
- Carbamoyl Aspartate → Dihydroorotate → Orotate (ring closure + oxidation)
- Orotate + PRPP → OMP (Orotidinyl Monophosphate) [OPRT]
- OMP → UMP [Orotidylate decarboxylase] — Deficiency = Orotic aciduria Type I (CPS-II not affected)
UMP → UDP → UTP → CTP [CTP Synthetase, Glutamine as N donor]
For DNA: Ribonucleotides → Deoxyribonucleotides by Ribonucleotide Reductase (RNR; inhibited by hydroxyurea).
dUMP → dTMP [Thymidylate Synthase — uses N5,N10-methylene-THF as methyl donor → DHF; requires regeneration by DHFR (target: Methotrexate, Trimethoprim)]
Pyrimidine Catabolism
Pyrimidines are degraded to highly soluble products (unlike purines → uric acid):
- Cytosine → Uracil → Dihydrouracil → β-Alanine + NH₃ + CO₂
- Thymine → Dihydrothymine → β-Aminoisobutyrate + NH₃ + CO₂
β-Alanine can be used to make carnosine (muscle buffer) or CoA. Easy to excrete — no equivalent of gout for pyrimidines.
Orotic Aciduria
- Type I: Deficiency of UMP synthase (OPRT + OMP decarboxylase activities). Megaloblastic anemia, orotic acid crystals in urine, failure to thrive. Treat: Uridine supplementation (bypasses the defect).
- OTC deficiency (urea cycle): Excess Carbamoyl-P spills to cytosol → ↑pyrimidine synthesis → ↑orotic acid. Key distinguishing feature: ↑NH₃ + ↑orotic acid.
Important Antimetabolites
- 5-Fluorouracil (5-FU): Converted to 5-FdUMP → irreversible inhibitor of Thymidylate Synthase (suicide inhibitor) → blocks dTMP synthesis → DNA synthesis halted. Used in colon, breast, head/neck cancers. Must be combined with leucovorin (folinic acid) to enhance activity.
- Cytarabine (Ara-C): Pyrimidine analog; inhibits DNA polymerase; used in AML.
- Gemcitabine: dFdCTP inhibits RNR and DNA polymerase; pancreatic cancer.
- Methotrexate, Trimethoprim: DHFR inhibitors → block both purine and pyrimidine synthesis.