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Biosynthesis of Pyrimidine Nucleotide

S-2-Biochemistry
2 min read
Full structural formula of Pyrimidine
Full structural formula of Pyrimidine

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:

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

Formation of Carbamoyl Aspartate

  • Carbamoyl phosphate reacts with aspartate to form carbamoyl aspartate, catalyzed by aspartate transcarbamoylase.

  • Reaction: Carbamoyl phosphate + Aspartate → Carbamoyl aspartate + Pi

Ring Closure

  • Carbamoyl aspartate is cyclized to form dihydroorotate by dihydroorotase.

  • Reaction: Carbamoyl aspartate → Dihydroorotate + H₂O

Oxidation

  • Dihydroorotate is oxidized to orotate by dihydroorotate dehydrogenase.

  • Reaction: Dihydroorotate + NAD⁺ → Orotate + NADH

Formation of Orotidine Monophosphate (OMP)

  • Orotate is combined with PRPP to form orotidine monophosphate by orotate phosphoribosyltransferase.

  • Reaction: Orotate + PRPP → OMP + PPi

Decarboxylation to UMP

  • OMP is decarboxylated to uridine monophosphate (UMP) by orotidine-5’-phosphate decarboxylase.

  • Reaction: OMP → UMP + CO₂

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.

Biosynthesis of Pyrimidine Nucleotide
Biosynthesis of Pyrimidine Nucleotide

Salvage Pathway

  • Similar to purines, pyrimidine bases and nucleosides can be salvaged.

Key enzymes include:

Uracil Phosphoribosyltransferase (UPRT)

  • Converts uracil to UMP.

  • Reaction: Uracil + PRPP → UMP + PPi

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. (Biosynthesis of Pyrimidine Nucleotide)


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