Catabolism and Salvage of Pyrimidine Nucleotides

Catabolism of the pyrimidine nucleotides leads ultimately to β-alanine (when CMP and UMP are degraded) or β-aminoisobutyrate (when dTMP is degraded) and NH3 and CO2. The β-alanine and β-aminoisobutyrate serve as -NH2 donors in transamination of α-ketoglutarate to glutamate. A subsequent reaction converts the products to malonyl-CoA (which can be diverted to fatty acid synthesis) or methylmalonyl-CoA (which is converted to succinyl-CoA and can be shunted to the TCA cycle).

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. However, as indicated above, the salvage pathway to thymidine nucleotide synthesis is especially important in the preparation for cell division. Uracil can be salvaged to form UMP through the concerted action of uridine phosphorylase and uridine kinase, as indicated:

uracil + ribose-1-phosphate <——> uridine + Pi

uridine + ATP ——> UMP + ADP

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

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.

The major function of the pyrimidine nucleoside kinases is to maintain a cellular balance between the level of pyrimidine nucleosides and pyrimidine nucleoside monophosphates. However, since the overall cellular and plasma concentrations of the pyrimidine nucleosides, as well as those of ribose-1-phosphate, are low, the salvage of pyrimidines by these kinases is relatively inefficient.

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