The Deoxyribonucleosides of Uracil & Cytosine are Salvaged
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p342-344
2025-09-01
464
Adenine, guanine, and hypoxanthine released during the turnover of nucleic acids, notably messenger RNAs, are recon verted to nucleoside triphosphates via so-called salvage path ways. While mammalian cells reutilize few free pyrimidines, “salvage reactions” convert the pyrimidine ribonucleosides uridine and cytidine and the pyrimidine deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides.
Guanine + PRPP → GMP + PPi
Hypoxanthine + PRPP → IMP + PPi
Phosphoryltransferases (kinases) catalyze transfer of the γ-phosphoryl group of ATP to the diphosphates of the dNDPs 2′-deoxycytidine, 2′-deoxyguanosine, and 2′-deoxyadenosine, converting them to the corresponding nucleoside triphosphates.
NDP + ATP→NTP + ADP
dNDP + ATP→ dNTP + ADP
Methotrexate Blocks Reduction of Dihydrofolate
The reaction catalyzed by thymidylate synthase, EC 2.1.1.45 (reaction 12, Figure 1) is the only reaction of pyrimidine nucleotide biosynthesis that requires a tetrahydrofolate derivative. During this reaction, the methylene group of N5,N10 methylene-tetrahydrofolate is reduced to the methyl group that is transferred to the 5-position of the pyrimidine ring, as well as dihydrofolate, the oxidized form of tetrahydrofolate. For further pyrimidine synthesis to occur, dihydrofolate must be reduced back to tetrahydrofolate. This reduction, catalyzed by dihydrofolate reductase (EC 1.5.1.3), is inhibited bymethotrexate. Dividing cells, which must generate TMP and dihydrofolate, are especially sensitive to inhibitors of dihydrofolate reductase such as the anticancer drug methotrexate.
Fig1. The biosynthetic pathway for pyrimidine nucleotides.
Certain Pyrimidine Analogs Are Substrates for Enzymes of Pyrimidine Nucleotide Biosynthesis
Allopurinol and the anticancer drug 5-fluorouracil are alternate substrates for orotate phosphoribosyltransferase, EC 2.4.2.10 (reaction ➄, Figure 1). Both drugs are phosphoribosylated, and allopurinol is con verted to a nucleotide in which the ribosyl phosphate is attached to N1 of the pyrimidine ring.
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