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