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Updated: Oct 27 2020

De Novo Nucleotide Synthesis

4.6

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(17)

  • Overview
    • Phosphoribosyl pyrophosphate (PRPP)
      • sugar building block formed in nucleotide synthesis
        • added to nitrogenous base to form nucleoside
      • formed from ribose-5-phosphate
        • product of pentose phosphate shunt
      • ATP + ribose-5-phosphate = PRPP + AMP
        • catalyzed by PRPP synthetase
      • once PRPP is made it can add to either a de novo or salvaged base
    • Pyrimidine
      • pathway diagram
      • important enzymes
        • carbamoyl phosphate synthetase-2
          • rate limiting step
          • not the same carbamoyl phosphate as in urea cycle
        • ribonucleotide reductase
          • inhibited by hydroxyurea
          • also reduces UDP, CDP, ADP, GDP
            • dADP and dATP negatively feedback and inhibit enzyme
          • result = ↓ dTMP, dUDP, dCDP, dADP, dGDP
            • note: good to target thymidine synthesis because it is not involved in RNA
        • thymidylate synthase
          • inhibited by 5-fluorouracil (5-FU)
          • result = ↓ dTMP
        • dihydrofolate reductase
          • inhibited by methotrexate (MTX) in eukaryotes
          • inhibited by trimethoprim (TMP) in prokaryotes
            • sulfamethoxazole (SMX) interferes with DHF synthesis in prokaryotes
            • co-trimoxazole = TMP + SMX
          • inhibited by pyrimethamine in protozoa
          • result = ↓ dTMP
      • deficiency
        • orotic aciduria
          • inability to convert orotic acid to UMP
          • defect in uridine monophosphate (UMP) synthase
          • AR
          • presentation
            • ↑ orotic acid crystals in urine
            • megaloblastic anemia
              • does not improve with administration of vitamin B12 or folic acid
              • not enough thymidine to sustain normal erythropoiesis
            • failure to thrive
            • no hyperammonemia
              • distinguishes between ornithine transcarbamylase (OTC) deficiency with high [orotic acid] in urine with hyperammonemia
          • treatment
            • oral uridine administration
              • bypasses defect in de novo pyrimidine pathway
    • purine
      • pathway diagram
      • insufficient capacity in most cells
      • important enzymes
        • PRPP amidotransferase
          • inhibited by AMP, GMP, IMP
          • rate-limiting step
          • indirectly inhibited by allopurinol
          • indirectly inhibited by 6-mercaptopurine
      • note: base of inosine hypoxanthine
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