1. Synthesis Of Pyrimidine Nucleotides By Salvage Pathway
Dr. Shumaila Asim
Lecture # 4

4. salvage of Uracil
The salvage of pyrimidine bases has less clinical significance than that of the purines, owing to the solubility of the by-products of pyrimidine catabolism.
Uracil can be salvaged to form UMP through the action of uridine phosphorylase and uridine kinase, as indicated:
uracil + ribose-1-phosphate <——> uridine + Pi
uridine + ATP ——> UMP + ADP

5. Salvage pathway of pyrimidine nucleotides
Uracil + PRPP
UMP + PPi
Uracil phosphate ribosyltransferase
Uracil + 1-phosphoribose
UMP +ADP
Uridine phosphorylase
Uracil ribonucleoside + ATP
Uridine kinase
UMP +ADP

6. salvage of Deoxyuridine
Deoxyuridine is also a substrate for uridine phosphorylase.
Formation of dTMP, by salvage of dTMP requires thymine phosphorylase and the previously encountered thymidine kinase:
thymine + deoxyribose-1-phosphate <——> thymidine + Pi
thymidine + ATP ——> dTMP + ADP

7. salvage of deoxycytidine
The salvage of deoxycytidine is catalyzed by deoxycytidine kinase:
deoxycytidine + ATP <——> dCMP + ADP
Deoxyadenosine and deoxyguanosine are also substrates for deoxycytidine kinase, although the Km for these substrates is much higher than for deoxycytidine.

8. salvage of thymidine
The salvage pathway to dTTP synthesis involves the enzyme thymidine kinase which can use either thymidine or deoxyuridine as substrate:
thymidine + ATP <——> TMP + ADP
deoxyuridine + ATP <——> dUMP + ADP
The activity of thymidine kinase (one of the various deoxyribonucleotide kinases) is unique in that it fluctuates with the cell cycle, rising to peak activity during the phase of DNA synthesis; it is inhibited by dTTP.

9. Synthesis of deoxyribonucleotides

10. Summary of pyrimidine biosynthesis
UMP

11. Catabolism of Pyrimidine Nucleotides

13. Degradation of pyrimidine nucleotide
The pyrimidine ring can be completely degraded in humans.
The products include: NH3, CO2, b-alanine, and b- aminoisobutyrate.
Both b-alanine, and b-aminoisobutyrate can be further converted into acetyl-CoA and succinyl-CoA, respectively, or are excreted in the urine.

18. Pyrimidine related disorders
Orotic acidurias
Deficiency of enzymes of urea cycle results in excretion of pyrimidine precursors

19. Pyrimidine Related Disorders
Orotic acidurias
Type – I
Deficiency of both orotate phospho-ribosyl transferase and orotidylate decarboxylase
Orotate & OMP cannot be converted to UMP ,CMP & TMP  Orotate & OMP accumulate  inhibition of DNA & RNA synthesis
Type – II
Deficiency of only orotidylate decarboxylase
OMP cannot be converted into UMP  inhibition of DNA / RNA synthesis

20. Pyrimidine Related Disorders
Deficiency of Urea Cycle enzymes
e.g. Deficiency of Ornithine trans-carbamoylase
Carbamoyl-phosphate cannot enter urea cycle
Exits into cytosol & stimulates pyrimidine synthesis
Leads to increased excretion of precursors of pyrimidines i.e. Orotic acid, uracil and orotidine

22. Assignment second week (Practical Copy)
A flow sheet describing Pyrimidine degradation with enzymes and co-enzymes marks
Tabulate the Inherited disorders of pyrimidine metabolism marks
Flow chart showing the De novo synthesis of pyrimidine nucleotides marks