Synthesis Of Pyrimidine Nucleotides By Salvage Pathway Dr. Shumaila Asim Lecture # 6

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

Salvage pathway of pyrimidine nucleotides Uracil + PRPP UMP + PPi Uracil phosphate ribosyltransferase Uracil ribonucleoside + ATP Uridine kinase UMP +ADP

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

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.

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.

Synthesis of deoxyribonucleotides

Summary of pyrimidine biosynthesis UMP

Catabolism of Pyrimidine Nucleotides

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.

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

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

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