Pyrimidine Synthesis

Step 1

Carbamoyl Phosphate: Glutamine + HCO₃⁻ + 2 ATP → carbamoyl phosphate via Carbamoyl Phosphate Synthetase II (CPSII) in the cytoplasm. This is the regulatory step: inhibited by CTP, activated by PRPP. (Contrast with CPSI, which uses ammonia, is mitochondrial, and functions in the urea cycle.)

Step 2

Carbamoyl Aspartate: Aspartate transcarbamoylase (ATCase) condenses carbamoyl phosphate with aspartate, releasing Pi and beginning assembly of the pyrimidine ring.

Step 3

Ring Closure to Dihydroorotate: Dihydroorotase closes the ring by removing water, converting carbamoyl aspartate into dihydroorotate.

Step 4

Oxidation to Orotate: Dihydroorotate dehydrogenase (using CoQ as electron acceptor) oxidizes dihydroorotate to orotate, completing the pyrimidine ring.

Step 5

Attach Ribose via PRPP: Orotate phosphoribosyl transferase adds PRPP to form OMP (orotidine monophosphate). Unlike purines, PRPP is added last.

Step 6

Decarboxylation to UMP: OMP decarboxylase removes CO₂ to yield UMP (uridine monophosphate). UMP is the precursor for all other pyrimidines.

Step 7

UMP → CTP and dTMP: CTP synthetase aminates UTP (using glutamine + ATP) to produce CTP. For thymine: dUMP + 5,10-methylenetetrahydrofolate → dTMP via thymidylate synthase (one-carbon metabolism).