Disorders of pyrimidine metabolism


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Orotic aciduria and pyrimidine metabolism

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Disorders of pyrimidine metabolism

  1. 1. Disorders of Pyrimidine Metabolism Lecturer: Dr. G. K. Maiyoh Department of Medical Biochemistry, School of Medicine, MUMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 1
  2. 2. Pyrimidines and Purines• Pyrimidine and purine are the names of the parent compounds of two types of nitrogen-containing heterocyclic aromatic compounds. N N N N N N H Pyrimidine Purine
  3. 3. Important Pyrimidines• Pyrimidines that occur in DNA are cytosine and thymine. Cytosine and uracil are the pyrimidines in RNA. O O NH2 CH3 HN HN HNO N O N O N H H H Uracil Thymine Cytosine
  4. 4. Synthesis Pathways• For both purines and pyrimidines there are two means of synthesis (often regulate one another) – de novo (from bits and parts) – salvage (recycle from pre-existing nucleotides) de novo Pathway Salvage Pathway
  5. 5. Many Steps Require an Activated Ribose Sugar (PRPP) 5’
  6. 6. de novo Synthesis• Committed step: This is the point of no return – Occurs early in the biosynthetic pathway – Often regulated by final product (feedback inhibition) X
  7. 7. Raw materials for biosynthesis O NH 2 • Synthesized C CH3 C H HN C N C from: – Glutamine O C C O C C N H N H – CO2 H H – Aspartic acid – Requires ATP Uracil Cytosine• Pyrimidine rings are synthesized independent of the ribose and transferred to the PRPP (ribose)• Generated as UMP (uridine 5’-monophosphate)
  8. 8. How is Pyrimidine Biosynthesisregulated? • Regulation occurs at first step in the pathway (committed step) • 2ATP + CO2 + Glutamine = carbamoyl phosphate X Inhibited by UTP If you have lots of UTP around this means you won’t make more that you don’t need. This is referred to as;
  9. 9. Biosynthesis: Purine vs Pyrimidine• Synthesized on PRPP • Synthesized then added to PRPP• Regulated by GTP/ATP • Regulated by UTP• Generates IMP • Generates UMP/CMP• Requires Energy • Requires Energy
  10. 10. Hereditary Orotic Aciduria• Is a defect in de novo synthesis of pyrimidines• Loss of functional UMP synthetase – Gene located on chromosome III• Characterized by excretion of orotic acid• Results in severe anemia and growth retardation• Extremely rare (15 cases worldwide)• Treated by feeding UMP
  11. 11. Why does UMP Cure Orotic Aciduria? Carbamoyl Phosphate Orotate XUMP Synthetase Feedback• Disease (-UMP) Inhibition – No UMP/excess orotate• Disease (+UMP) – Restore depleted UMP – Downregulate pathway via feedback inhibition (Less orotate)
  12. 12. Catabolism of pyrimidines• Animal cells degrade pyrimidines to their component bases.• Happen through dephosphorylation, deamination, and glycosidic bond cleavage.• Uracil and thymine broken down by reduction (vs. oxidation in purine catabolism).
  13. 13. Page 1098
  14. 14. Pyrimidine Degradation/Salvage• Pyrimindine rings can be fully degraded to soluble structures (Compare to purines that make uric acid)• Can also be salvaged by reactions with PRPP – Catalyzed by Pyrimidine phosphoribosyltransferaseDegradation pathways are quite distinct for purines and pyrimidines, but salvage pathways are quite similar