Biosynthesis of Pyrimidine

Biosynthesis of Pyrimidine

Objective

•       At the end of this lecture, student will be able to

–      Explain biochemical reactions of pyrimidine nucleotide biosynthesis

–      Discuss the degradation of pyrimidine nucleotides

–      Explain the disorders of pyrimidine metabolism

Biosynthesis of pyrimidine nucleotide

•       Synthesis of pyrimidine is simpler process then purine

•       Aspartate, Glutamine and CO₂ contribute the formation of pyrimidine ring

•       Here, pyrimidine ring is synthesized and then attached to ribose-5-phosphate 

Biosynthesis of pyrimidine nucleotide

1. Glutamine transfer the amino nitrogen to co₂ to produce carbamoyl phosphate in presence of carbamoyl phosphate synthase-II by utilizing  2 ATP and 1 molecule of H₂O
2. Carbmoyl phosphate condenses with aspartate to form carbamoyl aspartate in presence of Aspartate trans carbamoylase
3. Dihydroorotase catalyse the pyrimidine ring to close with a loss of H₂O  to form dihydroorotate
4. NAD⁺ dependent dihydroorotate dehydrogenase convert dihydrooratate to form orotate
5. Ribose-5-phosphate is added to orotate to produce orotidine monophosphate (OMP)
6. OMP undergoes decarboxylation by OMP decarboxylase to form Uridine monophosphate by releasing CO₂
7. UMP converts to UDP and finally to UTP by enzyme kinase which serves as a precursor for synthesis of dUMP, dTMP, UTP & CTP

Degradation of Pyrimidine nucleotides

•       Pyrimidine undergoes similar reaction

•       I.e. dephosphorylation, deamination and cleavage of glycosidic bond and liberate (cytosine, uracil & thymine)

•       These bases are then degraded to high soluble product, β-alanine & β- aminoisobutyrate

•       These are amino acid which undergoes transamination and other reaction to finally produce acetyl-CoA & succinyl-CoA

•       These compounds gets metabolise and excreted through urine

Disorders of pyrimidine metabolism

•       Orotic aciduria

Metabolic disorder characterised by excretion of orotic acid in urine, which leads to severe anaemia and retarded growth.

Due to deficiency of enzyme orotate phosphoribosyl transferase and OMP decarboxylase

•       Reye’s syndrome

Due to defect in ornithine transcarbamoylase which led to accumulation of carbamoyl phosphate and cause increase synthesis & excretion of orotic acid

Summary

• Aspartate + Glutamine + Co₂ contribute for pyrimidine ring
• Proceeds only in a cytoplasm of cells
• Degradation of pyrimidine nucleotides occurs by dephosphorylation, deamination and cleavage of glycosidic bond.
• Orotic aciduria  & Reye’s syndrome are the common disorders of pyrimidine nucleotides metabolism