Nucleotide Catabolism/Salvage

Overview

•  Purine
  • salvage pathway
    • see figure
  • clinical importance
    • adenosine deaminase (ADA) deficiency 
      • defective purine salvage
        • results in excess ATP and dATP
      • prevents DNA synthesis
        • ATP and dATP feedback negatively on ribonucleotide reductase in the synthesis of purines and pyrimidines for DNA replication
        • ↓ lymphocyte count
          • major cause of SCID (severe combined immunodeficiency disease)
            • lack of both T and B cells
      • AR
    • Lesch-Nyhan disease  
      • defective purine salvage
      • lacks hypoxanthine guanine phosphoribosyl pyrophosphate transferase (HGPRT) enzyme
        • responsible for phosphoribosyl group transfer 
      • X-linked recessive 
      • presentation
        • severe CNS symptoms
          • choreoathetosis
          • mental retardation
        • self-mutilation
        • hyperuricemia
          • degradation of all purines since it cannot salvage
    • gout
      • pathophysiology
        • high urate levels due to
          • ↑ in cell breakdown
            • e.g. treatment of large tumor masses with radiation or chemo
          • ↓ in renal excretion (most common cause)
        • results in precipitation of monosodium urate crystals in joints
          • negative birefringence
            • yellow when parallel to slow ray
          • needle shaped
      • presentation
        • recurrent acute arthritis
          • pain in big toe first (podagra)
        • chronic
          • tophi present
            • granulomatous deposition (multinucleated giant cells) of crystals in soft tissue
        • ↑ frequency in men >30 y/o
      • treatment
        • acute → colchicine or indomethacin
        • chronic due to ↓ in renal excretion → probenecid
        • chronic due to ↑ in cell breakdown → allopurinol
• Pyrimidine
  • salvage
    • may be salvaged by pyrimidine salvage enzymes
  • degradation
    • completely broken down to ammonia
• Other causes of hyperuricemia
  • ↑ EtOH intake
    • can precipitate an acute gout attack
  • ↑ nucleic acid in diet
    • red meats, organ meats
  • phosphate “trapping” diseases
    • e.g. glucose-6-phosphate deficiency (G6PD), galactose uridyltransferase deficiency
    • caused by an inability to dephosphorylate common metabolites and therefore leads to trapping of phosphate by these metabolites
    • lack of phosphate prevents synthesis of ATP, GTP, plus other nucleotide phosphates
• ADP. AMP, and other hypophosphorylated bases are salvaged producing uric acid