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26 porphyria

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SMC, JSMU, MBBS, Blood module

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26 porphyria

  1. 1. ENZYMES A protein with catalytic properties due to its power of specific activation © 2007 Paul Billiet ODWS
  2. 2. ObjectivesObjectives • Understand the structure of HemeUnderstand the structure of Heme • Identify the rate limiting stepIdentify the rate limiting step • Describe the site of effect of certain drugs on hemeDescribe the site of effect of certain drugs on heme biosynthesis and its clinical importancebiosynthesis and its clinical importance • Identify how blocking in one of the enzyme involved inIdentify how blocking in one of the enzyme involved in heme biosynthesis will affect the mode of presentation ofheme biosynthesis will affect the mode of presentation of the diseasethe disease • Identify the most common type of porphyrias & its causeIdentify the most common type of porphyrias & its cause
  3. 3. Abnormalities in synthesis heme (porphyrias)
  4. 4. Objectives   By the end of this lecture the student should be able to:   Understand the porphyrias  Describe the site of effect of certain drugs on heme biosynthesis and its clinical importance  Identify how blocking in one of the enzyme involved in heme biosynthesis will affect the mode of presentation of the disease.  Identify the most common type of porphyrias & its cause
  5. 5. HEMOGLOBIN SYNTHESIS
  6. 6. Structure of heme prosthetic group Protoporphyrin ring w/ iron =Protoporphyrin ring w/ iron = hemeheme Four Pyrrole groups [A to D]Four Pyrrole groups [A to D] linked by methane bridgeslinked by methane bridges FeFe+2+2 coordinated by prophyrin Ncoordinated by prophyrin N atoms and a N from Histidineatoms and a N from Histidine (blue)(blue) A molecule of OA molecule of O22 acts as 6acts as 6thth ligandligand
  7. 7. Heme structure Heme is a metaloporphyrine (cyclic tetrapyrrole) Heme contains:  conjugated system of double bonds → red colour  4 nitrogen (N) atoms  1 iron cation (Fe2+ ) → bound in the middle of tetrapyrrole skelet by coordination covalent bonds methine bridge pyrrole ring
  8. 8. Properties of iron in heme • Coordination number of iron in heme = 6 6 bonds: • 4x pyrrole ring (A,B,C,D) • 1x link to a protein • 1x link to an oxygen
  9. 9. Heme biosynthesis - repetition • in bone marrow (85% of Hb) and liver (cytochromes) • cell location: mitochondria / cytoplasm / mitochondria • substrates: succinyl-CoA + glycine • important intermediates:  δ-aminolevulinic acid (= 5-aminolevulinic acid, ALA)  porphobilinogen (PBG = pyrrole derivate)  uroporphyrinogen III (= porphyrinogen – heme precursor)  protoporphyrin IX (= direct heme precursor) ● key regulatory enzyme: ALA synthase
  10. 10. Regulation of heme biosynthesis  ALA synthase is a key regulatory enzyme ● it is an allosteric enzyme that is inhibited by an end product - heme (feedback inhibition) ● requires pyridoxal phosphate as a coenzyme ● certain drugs and steroid hormones can increase heme synthesis  Porphobilinogen synthase is inhibited by lead ions Pb2+ in case of lead poisoning.  Ferrochelatase (heme synthase) can be also inhibited by Pb2+ . Its activity is influenced by availability of Fe2+ and ascorbic acid.
  11. 11. Porphyrias - disturbances of heme synthesis • are hereditary or acquired disturbances of heme synthesis • in all cases there is an identifiable abnormality of the enzymes which synthesize heme • this leads to accumulation of intermediates of the pathway and a deficiency of heme → excretion of heme precursors in feces or urine, giving them a dark red color ● accumulation of porphyrinogens in the skin can lead to photosensitivity • the neurological symptoms
  12. 12. Disorders of Heme Synthesis  Acquired: Lead poisoning  Congenital: Porphyrias
  13. 13. LEAD TOXICITY Mechanism • Binds to any compound with a sulfhydryl group • Inhibits multiple enzyme reactions including those involved in heme biosynthesis (ALA synthase & ferrochelatase) • One symptom of lead toxicity is increases in 5- ALA without concomitant increases in PBG
  14. 14. Porphyria Cutanea TardaPorphyria Cutanea Tarda  Chronic hepatic porphyria  The most common type of porphyria  a deficiency in uroporphyrinogen decarboxylaseuroporphyrinogen decarboxylase  Clinical expression of the enzyme deficiency is influenced by various factors, such as exposure to sunlight, the presence of hepatitis B or C  Clinical onset is during the fourth or fifth decade of life.  Porphyrin accumulation leads to cutaneous symptomscutaneous symptoms and urineurine that is red to brown in natural light and pink to red in fluorescent light
  15. 15. (1) Porphyria cutanea tarda:
  16. 16. Symptoms of Cutaneous Forms Occur most commonly with exposure to sunlight Mainly skin symptoms that occur Due to excess poryphorins that accumulate in surface of skin Symptoms:  Fluid filled blisters  Changes in pigmentation  Breakdown (necrosis) of the skin when exposed to sunlight  Overall skin can become scarred, brown, blotchy and fragile
  17. 17. Treatment for Cutaneous Forms  Avoiding sunlight  Attention to skin care  Beta-carotene supplements  Function to neutralize the effects of reactive protoporphyrins
  18. 18. Acute Hepatic PorphyriasAcute Hepatic Porphyrias e.g. Acute Intermittent Porphyria  Porphyrias leading to accumulation of ALA and porphobilinogen cause abdominal pain and neuropsychiatric disturbances, ranging from anxiety to delirium.  Symptoms of the acute hepatic porphyrias are often precipitated by administration of drugs such as barbiturates and ethanol.
  19. 19. Porphyrias (A) Acute intermittent Porphyria:  An acute disease caused by a deficiency in hydroxymethylbilane synthase.  Porphobilinogen and δ-aminolevulinic acid accumulate in the urine.  Urine darkens on expoure to light and air.  Patients are not photosenstive
  20. 20. Porphyrias : Acute hepatic Porphyrias (2) Hereditary coproPorphyria:  An acute disease caused by a deficiency in coproPorphyrinogen oxidase  CoproPorphyrinogen lll and other intermediates prior to the block accumulate in the urine.  Patients are photosenstive.
  21. 21. Porphyrias : Acute hepatic Porphyrias (3) Varigate Porphyria:  An acute disease caused by a deficiency in protoporphyrinogen oxidase .  ProtoPorphyrinogen lX and other intermediates prior to the block accumulate in the urine.  Patients are photo-senstive.
  22. 22. Porphyrias Erythropoietic Porphyrias
  23. 23. (1) Erythropoietic Porphyrias:  The disease caused by a deficiency in ferrochelates.  ProtoPorphyrin accumulate in the erythrocytes, bone marrow and plasma  Patients are photosenstive.
  24. 24. (2) Congenital erythropoietic Porphyrias:  The disease caused by a deficiency in uroporphyrinogen lll synthase.  Uroporphyrinogen l & coproPorphyrinogen l accumulate in urine  Patients are photosenstive.
  25. 25. Overall Pathway
  26. 26. Overall pathway
  27. 27. ALA Synthetase Most important rate limiting enzyme Deficiency may cause  Sideroblastic anemia Bone marrow produces ringed sideroblast? Respond to pyridoxine treatment
  28. 28. Overall pathway
  29. 29. ALA dehydratase deficiency  Autosomal recessive  Very rare Aminolevulinic Acid Porphobilinogen ALA dehydratase
  30. 30. Overall pathway
  31. 31. Acute intermittent porphyria (AIP)  2nd most common form of porphyria  Caused by deficiency of PGB deaminase  Metabolite porphobilinogen accumulates in cytoplasm  raised concentration of urinary porphyrins Porphobilinogen (PGB) PGB deaminase Hydroxymethylbilane
  32. 32. Overall pathway
  33. 33. Congenital erythropoietic porphyria (CEP)  Deficiency of Uroporphyrinogen III synthase  Severe photosensitivity Hydroxymethylbilane Uroporphyrinogen III Uroporphyrinogen III synthase
  34. 34. Overall pathway
  35. 35. Porphyria cutanae tarda (PCT) Most common porphyria Classified as such when Uroporphyrinogen decarboxylase activity <20% Inherited or obtained through Hepatitis C, alcohol, Uroporphyrinogen III Uroporphyrinogen decarboxylase Coproporphyrinogen III
  36. 36. Overall pathway
  37. 37. Hereditary coproporphyria:  Deficiency of Coproporphyrinogen III Oxidase  Autosomal dominant  No cure exists
  38. 38. Overall pathway
  39. 39. Variegate porphyria  Deficiency in protoporphyrinogen IX-oxidase  Autosomal dominant
  40. 40. Overall pathway
  41. 41. Erthropoietic Protoporhyria Caused by deficiency of Ferrochelatase Autosomal dominant Photosensitivity- can be managed by limiting exposure
  42. 42. Thank You!

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