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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
        • rate-limiting step
        • inhibited by AMP, GMP, IMP
        • indirectly inhibited by allopurinol
        • indirectly inhibited by 6-mercaptopurine
    • note: base of inosine = hypoxanthine
 

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