Biosynthesis of Pyrimidine Nucleotide

• Biosynthesis of Pyrimidine Nucleotide is the biochemical process through which cells produce pyrimidine bases cytosine, thymine, and uracil used to form nucleotides such as UMP (uridine monophosphate), CMP (cytidine monophosphate), and TMP (thymidine monophosphate).
• Biosynthesis of Pyrimidine Nucleotide is synthesized first and then attached to a ribose-phosphate backbone.

De Novo Pathway

• The de novo synthesis of pyrimidines begins with the formation of a basic pyrimidine ring that is then attached to ribose-5-phosphate.
• Here’s a detailed outline:

1. Formation of Carbamoyl Phosphate:

   • Carbamoyl phosphate is synthesized from glutamine, CO₂, and ATP by the enzyme carbamoyl phosphate synthetase II.
   • Reaction: Glutamine + CO₂ + 2 ATP → Carbamoyl phosphate + Glutamate + 2 ADP + Pi

2. Formation of Carbamoyl Aspartate:

   • Carbamoyl phosphate reacts with aspartate to form carbamoyl aspartate, catalyzed by aspartate transcarbamoylase.
   • Reaction: Carbamoyl phosphate + Aspartate → Carbamoyl aspartate + Pi

3. Ring Closure:

   • Carbamoyl aspartate is cyclized to form dihydroorotate by dihydroorotase.
   • Reaction: Carbamoyl aspartate → Dihydroorotate + H₂O

4. Oxidation:

   • Dihydroorotate is oxidized to orotate by dihydroorotate dehydrogenase.
   • Reaction: Dihydroorotate + NAD⁺ → Orotate + NADH

5. Formation of Orotidine Monophosphate (OMP):

   • Orotate is combined with PRPP to form orotidine monophosphate by orotate phosphoribosyltransferase.
   • Reaction: Orotate + PRPP → OMP + PPi

6. Decarboxylation to UMP:

   • OMP is decarboxylated to uridine monophosphate (UMP) by orotidine-5’-phosphate decarboxylase.
   • Reaction: OMP → UMP + CO₂

7. Conversion to other Pyrimidines:

   • UMP to UDP and UTP: UMP is phosphorylated by kinases to form UDP and then UTP.
   • UTP to CTP: UTP is aminated to form CTP by CTP synthetase, using glutamine as the nitrogen donor.

Salvage Pathway

• Similar to purines, pyrimidine bases and nucleosides can be salvaged.
• Key enzymes include:

  1. Uracil Phosphoribosyltransferase (UPRT):

     • Converts uracil to UMP.
     • Reaction: Uracil + PRPP → UMP + PPi

  2. Thymidine Kinase (TK) and Uridine-Cytidine Kinase (UCK):

     • Phosphorylate pyrimidine nucleosides (thymidine, uridine, cytidine) to their corresponding monophosphates (TMP, UMP, CMP).

Regulation

• The biosynthesis of nucleotides is tightly regulated through feedback inhibition to ensure balance and meet cellular demands:

  • Pyrimidine Synthesis:

    • Carbamoyl phosphate synthetase II is inhibited by UTP and activated by ATP and PRPP

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