Biosynthesis and Degradation of Pyrimidines
Pyrimidines include cytosine, thymine and uracil. Unlike purines, the pyrimidine ring is synthesized first, then attached to ribose-5-phosphate.
De Novo Biosynthesis of Pyrimidines
- The process begins with carbamoyl phosphate, which is synthesized in the cytosol by Carbamoyl Phosphate Synthetase II (CPS II).
- CPS II uses glutamine, CO₂, and ATP and is the key regulatory enzyme of pyrimidine synthesis.
- CPS II is inhibited by UTP and activated by PRPP.
- Carbamoyl phosphate is combined with aspartate to form carbamoyl aspartate, which is then cyclized to produce dihydroorotate.
- Dihydroorotate is oxidized to orotate.
- Orotate reacts with PRPP (from the pentose phosphate pathway) to form OMP (orotidine monophosphate).
- OMP decarboxylase then converts OMP to UMP (uridine monophosphate).
- From UMP → UDP → UTP.
- UTP can be converted to CTP by adding an amine group (from glutamine).
- To make thymidine nucleotides, UMP → UDP → dUDP → dUMP → thymidylate (dTMP) via:
- Thymidylate synthase
- Requires tetrahydrofolate (THF) as a one-carbon donor.
Regulation of Pyrimidine Synthesis
- CPS II is the main regulatory step.
- UTP provides feedback inhibition.
- High PRPP stimulates synthesis, signaling high need for nucleotides.
Degradation of Pyrimidines
- Pyrimidines degrade into β-alanine, β-aminoisobutyrate, CO₂, and NH₃.
- These products are water-soluble and easily excreted.
- Unlike purines (which form uric acid), pyrimidine degradation does not cause gout.