Pyrimidine Synthesis Pathway: Synthesis of pyrimidine derivatives
The pyrimidine synthesis is a similar process than that of Purines(Purines Synthesis). In the de novo synthesis of Pyrimidines, the ring is synthesized first and then it is attached to a ribose-phosphate to for a pyrimidine nucleotide. Pyrimidine rings are assembled from bicarbonate, aspartate and Ammonia.
The pyrimidine biosynthesis (de novo pyrimidine synthesis pathway) was first observed in mutants of bread mole Neurospora Crassa, which are unable to synthesize pyrimidine, therefore, require both cytosine and Uracil in their growth medium.
Source of Atoms in Pyrimidine Ring:
- N1, C4, C5 and C6 → Comes from Aspartate
- N3 → Comes from Glutamine
- C2 → Comes from HCO3– (Carbonic acid)
Steps of Pyrimidine Synthesis:
This is one of the nucleic acid synthesis pathways. In the Pyrimidines, there are three Nucleotide molecules; they are UTP, CTP and TTP. The De novo pyrimidine synthesis pathway can be explained by the following steps.
- Synthesis of Carbamoyl Phosphate
- Synthesis of Carbamoyl Aspartate
- Ring Closure to form dihydro orotate
- Oxidation of Dihydro Orotate
- Addition of ribose Phosphate moiety
- De Carboxylation to form UMP
Step 1: Synthesis of Carbamoyl Phosphate:
- The first reaction of Pyrimidine synthesis is the synthesis of Carbamoyl phosphate by utilizing amide form of Glutamine (Glutamate) and HCO3– (Carbonic acid).
- This reaction is catalyzed by Carbamoyl phosphate synthetase-II, the enzyme is cytosolic enzyme is a cytosolic enzyme.
- In this reaction, 2 ATP molecules are consumed.
HCO3– (Carbonic acid) + Glutamine (Gln)
→ Carbamoyl Phosphate + 2 AMP
Step 2: Synthesis Carbamoyl Aspartate:
- Carbamoyl phosphate is condensing with Aspartic acid it forms carbamoyl aspartate is catalyzed by Aspartate Transcarbamoylase (ATCase).
Carbamoyl Phosphate + Aspartate
→ Carbamoyl Aspartate + H3PO4
Step 3: Ring Closure to form dihydroorotate:
- Carbamoyl Aspartate is converted into Dihydro Orotate by ring closure mechanism.
- This reaction is catalyzed by Dihydro Orotase.
Carbamoyl Aspartate → Dihydro Orotate + H20
Step 4: Oxidation of dihydroorotate:
- The hydro Orotate irreversibly oxidized to Orotate by the enzyme Dihydro Orotate Dehydrogenase.
- The Eukaryotic enzyme, which contains FMN and Non-heme iron, is located on the outer surface of the inner mitochondrial membrane where quinines supply its oxidizing power.
Dihydro Orotate + Quinone
→ Orotate + Reduced Quinone
Step 5: Addition of Ribose-Phosphate Moiety:
- Orotate reacts with PRPP to yield Orotidine-5-MonoPhosphate (OMP).
- This reaction is catalyzed by Orotate Phosphoribosyl transferase.
- In this reaction, pyrophosphate is released from the PRPP molecules.
Orotate + PRPP → OMP + PPi
Step 6: Decarboxylation to form UMP:
- The final reaction of the pathway is the decarboxylation of OMP by the OMP decarboxylase to form UMP this is an unusual reaction in that it requires no cofactors.
OMP → UMP + CO2
Synthesis of UTP and CTP:
- The synthesis of UTP forms UMP done by phosphate exchange mechanism.
- This reaction is catalyzed by nucleoside monophosphate kinase and Nucleoside diphosphate Kinase.
UMP + ATP ↔ UDP + ADP
UDP + ATP ↔ UTP + ADP
CTP is formed by amination of UTP by CTP synthetase. In animals, the amino group is donated by Glutamine where as in bacteria it is supplied directly in Ammonia.
UTP + Gln +ATP + H2O → CTP + Glu + ADP + Pi
The Synthesis of pyrimidine derivatives are TTP, CTP and UTP.