Nucleotide METABOLISM MUHAMMAD MUSTANSAR

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PURINES PYRIMIDINES

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Nucleotide METABOLISM MUHAMMAD MUSTANSAR

  1. 1. Metabolism ofPurines and Pyrimines Dr Muhammad Mustansar
  2. 2. Origin of atoms in pyrimidine ring
  3. 3. Biological significance ofnucleotidemake up nucleic acids (DNA• Nucleotides metabolism and RNA)• Nucleotide triphosphates are the “energy carriers” in cells (primarily ATP)• Many metabolic pathways are regulated by the level of the individual nucleotides – Example: cAMP regulation of glucose release• Adenine nucleotides are components of many of the coenzymes + +
  4. 4. Dietary nucleotides• do not contribute energy as do carbs, proteins and fats• are not incorporated into RNA or DNA unless given I.V.• normally metabolized to individual components (bases, sugar and phosphate)• purines are converted to uric acid which is then excreted
  5. 5. Medical significance ofnucleotide metabolism• Anticancer agents: • Rapidly dividing cells biosynthesize lots of purines and pyrimidines, but other cells reuse them. Cancer cells are rapidly dividing, so inhibitor of nucleotide metabolism kill them• Antiviral agents – Zidovudine (Retrovir) – Lamivudine (Epivir) – Valacyclovir (Valtrex)
  6. 6. Structures of nucleotidebuilding blocks and nucleotides 6 7 4 5 N 5 1 N 3N 8 2 2 6 N 4 N N 9 3 H 1 PURINE PYRIMIDINE
  7. 7. Structures of nucleotide building NH2 blocks and nucleotides O O O NH 2 CH 3 N N HN HNN N N N H2N N N O N O N O N N H H H H H ADENINE GUANINE THYMINE URACIL CYTOSINE guanine: comes from guano; thymine –thymus gland
  8. 8. OH OH Base BaseOH P O CH 2 OH P O CH 2 O O O H H O H H H H H H OH OH OH H RIBONUCLEOTIDE DEOXYRIBONUCLEOTIDE Ribonucleotide – phosphate = ribonucleoside
  9. 9. Biosynthesis of the purine nucleotide system
  10. 10. The big picture
  11. 11. Steps 1 thru 3• Step 1:Activation of ribose-5- phosphate – enzyme: ribose phosphate pyrophosphokinase – product: 5-phosphoribosyl-α- pyrophosphate (PRPP) – PRPP is also a precursor in the biosynthesis of pyrimidine nucleotides and the amino acids histidine and
  12. 12. Step 1: purine synthesis
  13. 13. Steps 1 thru 3 • Step 2: acquisition of purine atom 9 – enzyme: amidophosphoribosyl transferase – displacement of pyrophosphate group by glutamine amide nitrogen (inversion of configuration – α to β – product: β-5-phosphoribosylamineSteps 1 and 2 are tightly regulated by feedback inhibition
  14. 14. Step 2: purine synthesis:commited step
  15. 15. Steps 1 thru 3• Step 3: acquisition of purine atoms C4, C5, and N7 – enzyme: glycinamide synthetase β-phosphoribosylamine reacts with ATP and glycine – product: glycinamide ribotide (GAR)
  16. 16. Step 3 : purine synthesis
  17. 17. Steps 4 thru 6• Step 4: acquisition of purine atom C8 – formylation of free α-amino group of GAR – enzyme: GAR transformylase – co-factor of enzyme is N10-formyl THF• Step 5: acquisition of purine atom N3 – The amide amino group of a second glutamine is transferred to form formylglycinamidine ribotide (FGAM)• Step 6: closing of the imidazole ring or formation of 5- aminoimidazole ribotide
  18. 18. Step 6: purine synthesis
  19. 19. Step 7• Step 7: acquisition of C6 – C6 is introduced as HCO3- – enzyme: AIR carboxylase (aminoimidazole ribotide carboxylase) – product: CAIR (carboxyaminoimidazole ribotide) – enzyme composed of 2 proteins: PurE and PurK (synergistic proteins)
  20. 20. Step 7: purine synthesis
  21. 21. Steps 8 thru 11• Step 8: acquisition of N1 – N1 is acquired from aspartate in an amide condensation reaction – enzyme: SAICAR synthetase – product: 5-aminoimidazole-4-(N- succinylocarboxamide)ribotide (SAICAR) – reaction is driven by hydrolysis of ATP
  22. 22. Step 8: purine synthesis
  23. 23. Steps 8 thru 11• Step 9: elimination of fumarate – Enzyme: adenylosuccinate lyase – Product: 5-aminoimidazole-4- carboxamide ribotide (AICAR)• Step 10: acquisition of C2 – Another formylation reaction catalyzed by AICAR transformylase – Product: 5-formaminoimidazole-4- carboxamide ribotide (FAICAR)
  24. 24. Step 9: purine synthesis
  25. 25. Step 10: purine synthesis
  26. 26. Step 11• cyclization or ring closure to form IMP• water is eliminated• in contrast to step 6 (closure of the imidazole ring), this reaction does not require ATP hydrolysis• once formed, IMP is rapidly converted to AMP and GMP (it does not accumulate in cells
  27. 27. Step 11: purinesynthesis
  28. 28. Lesch-Nyhan syndrome• there is a defect or lack in the HGPRT enzyme• the rate of purine synthesis is increased about 200X• uric acid level rises and there is gout• in addition there are mental aberrations• patients will self-mutilate by biting lips and fingers off
  29. 29. Lesch-Nyhan syndrome
  30. 30. Adenosine deaminase
  31. 31. ADA deficiency• In the absence of ADA lymphocytes are destroyed• deoxyadenosine is not destroyed, is converted to dAMP and then into dATP• dATP is a potent feedback inhibitor of deoxynucleotide biosynthesis• this leads to SCID (severe combined immunodeficiency disease)• Infants with this deficiency have a high fatality rate due to infections
  32. 32. ADA deficiency• treatment consists of administering pegylated ADA which can remain in the blood for 1 – 2 weeks• more efficient is gene therapy: replacing the gene that is missing or defective• gene therapy has been performed on selected patients
  33. 33. Adenosine deaminase
  34. 34. ADA deficiency• In the absence of ADA lymphocytes are destroyed• deoxyadenosine is not destroyed, is converted to dAMP and then into dATP• dATP is a potent feedback inhibitor of deoxynucleotide biosynthesis• this leads to SCID (severe combined immunodeficiency disease)• Infants with this deficiency have a high fatality rate due to infections
  35. 35. ADA deficiency• treatment consists of administering pegylated ADA which can remain in the blood for 1 – 2 weeks• more efficient is gene therapy: replacing the gene that is missing or defective• gene therapy has been performed on selected patients
  36. 36. O O H N H N N N H 2N N N O N N Ribose-P H Ribose-P H 2O H2O nucleotidase nucleotidase Pi PiDegradation of O O HGMP and XMP N N H N N H 2N N N O N N Pi Ribose Ribose PNP H Ribose-1P Pi PNP Ribose-1P O O H N N H N N H2N N N H2O NH3 N O N H H H
  37. 37. NH2 OH N NN N N N N N H 2N N N N N H H H ADENINE GUANINE(6-AMINOPURINE) 2-AMINO-6-OXYPURINE) PURINE OH OH OH N N NN N N OH N HO N N N N HO N H H HHYPOXANTHINE XANTHINE URIC ACID(6-OXYPURINE) (2,6-DIOXYPURINE) (LACTIM FORM)
  38. 38. CATABOLISM OF PURINESADENINE + H O 2 adenase HYPOXANTHINE + AMMONIA guanase XANTHINE + AMMONIAGUANINE + H2O xanthineHYPOXANTHINE + O2 + H2O oxidase XANTHINE + H2O2 xanthineXANTHINE + O2 + H20 URIC ACID + H2O2 oxidase
  39. 39. O O H N H N N N N N N O N O2 H202 H H H HYPOXANTHINE XANTHINE O2 H202 O O HH N H N N N OH OO N N N O N H H H H acidic proton URIC ACID
  40. 40. GOUT• a disorder associated with abnormal amounts of urates in the body• early stage: recurring acute non- articular arthritis• late stage: chronic deforming polyarthritis and eventual renal complication• disease with rich history dating back to ancient Greece
  41. 41. GOUT• once fashionable to associate gout with intelligence• people with gout: – Isaac Newton – Benjamin Frankin – Martin Luther – Charles Darwin – Samuel Johnson
  42. 42. Gout• prevails mainly in adult males• rarely encountered in premenopausal women• symptoms are cause by deposition of crystals of monosodium urate monohydrate (can be seen under polarized light)• usually affect joints in the lower extremities (the big toe is the classic
  43. 43. Gout
  44. 44. Four Stages of Gout1. asymptomatic hyperuricemia2. acute gouty arthritic attacks3. asymptomatic intercritical period4. tophaceous gout (characterized by the formation of tophi in joints) – podagra (big toe) – cheiagra (wrist) according to Hippocrates – gonadra (knee)
  45. 45. Diagnostic features• usually affect joints in the lower extremities ( 95%)• onset is fast and sudden• pain is usually severe; joint may be swollen, red and hot• attack may be accompanied by fever, leukocytosis and an elevated ESR
  46. 46. Drugs which may inducehyperuricemia• niacin• thiazides and other diuretics• low dose aspirin• pyrazinamide• ethambutol• cyclosporine• cytotoxic drugs
  47. 47. Non-pharmacologicalapproaches foods:• Avoid purine rich – red meat and organ meat (liver, kidneys) – shellfish, anchovies, mackerel, herring – meat extracts and gravies – peas and beans, aspargus, lentils – beer, lager, other alcoholic beverages• Weight loss• Control alcohol (binge drinking)
  48. 48. Pharmacological management of• gout on the premise that the based hyperuricemia is due to both overproduction and underexcretion of uric acid• symptomatic relief of pain is also achieved with analgesics (i.e. indomethacin)• drugs used: – analgesics (NSAIDs) – uricosuric agents – xanthine oxidase inhibitors
  49. 49. Therapy of acute gout• treat with colchicine or NSAIDs• avoid aspirin• do not treat with allopurinol or uricosuric drugs• uric acid lowering agents should never be started or stopped during acute attack• pain resolution occurs within 48-72
  50. 50. ColchicineCH3O H NCH3O C CH3 O OCH3 O OCH3 COLCHICINEa non-basic alkaloid from the seeds and corms of Colchicum autumnale (Meadow Safron)
  51. 51. COLCHICINE• used in the symptomatic treatment of acute attacks of gout• decreases leukocyte motility, decreases phagocytosis and lactic acid production• not used in other forms of arthritis• a very potent drug• can cause severe GI distress and abdominal pain
  52. 52. Probenecid (Benemid) O C3H7 HO2C S N O C3H7 PROBENECID (BENEMID)A uricosuric agent
  53. 53. Probenecid (Benemid)• inhibits the tubular reabsorption of uric acid• it can also inhibit the tubular excretion of certain organic acid via the transporter• used in gout to promote the elimination of uric acid (not effective in acute attack)• also used to enhance plasma concentration of certain antiinfectives (beta lactams)
  54. 54. ALLOPURINOL (Zyloprim)• prevention of attacks of gouty arthitis and nephropathy• also used during chemotherapy of cancer and to prevent recurrent calcium oxalate calculi• metabolized to oxypurinol (also an inhibitor of xanthine oxidase)• inhibits the metabolism of certain anticancer drugs (6-MP, azathioprine)
  55. 55. Allopurinol (Zyloprim) OH N N N N H ALLOPURINOL (ZYLOPRIM)An inhibitor of xanthine oxidase; prevents the formation of uric acid from precursorial purines
  56. 56. Fate of uric acid• in human and other primates uric acid is the final product of purine degradation and is excreted in the urine• the same is true in bird, reptiles and many insects• in other mammals uric acid is oxidized to allantoin (urate oxidase)• teleost (bony) fish convert allantoin to allantoic acid• cartilaginous fish and amphibian further degrade allantoic acid to urea• and finally marine invertebrates decompose urea to ammonia
  57. 57. O H HH N urate oxidase O N N O NH2 OO N N CO2 O N N ALLANTOIN H H H H H URIC ACID allantoinase O allantoicase H2N COOH NH2 H2N C NH2 UREA glyoxylic acid O N N O H H H ALLANTOIC ACID
  58. 58. Rasburicase (Elitek) A recombinant form of uric acid oxidase. Used for initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.
  59. 59. Catabolism of a pyrimidine

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