questions 3

De Novo Nucleotide Synthesis

Topic updated on 10/10/17 7:52pm

  • 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


Qbank (2 Questions)

(M1.BC.4707) A 12-year-old African American female presents to the emergency department with acute chest pain and swelling of hands and feet after running with her friends. She has previously had numerous episodes of fatigue and bone pain and a family history shows several relatives with anemia. A peripheral blood smear is performed and the results are shown in the photograph (Figure A). After confirmation of the diagnosis, she is prescribed a drug that is designed to alleviate the disorder by increasing the level of circulating fetal hemoglobin. Which of the following enzymes is affected by the medication that was most likely prescribed in this case? Topic Review Topic
FIGURES: A          

1. Dihydrofolate reductase
2. Inosine monophosphate (IMP) dehydrogenase
3. Methionine synthase
4. Pyruvate kinase
5. Ribonucleotide reductase

(M1.BC.6237) A 9-month-old female infant presented with failure to thrive, repeated respiratory infections, and anemia refractory to administration of cobalamin, pyridoxine, folic acid, and iron (Figure A). Urinalysis demonstrated a crystalline sediment and a blood test showed normal ammonia levels. Which of the following pathways is defective in this infant? Topic Review Topic
FIGURES: A          

1. Ornithine transcarbamoylase
2. Adenosine deaminase
3. Hypoxanthine-guanine phosphoribosyltransferase
4. Xanthine oxidase
5. UMP synthase

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