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Heme synthesis and degradation
- 3. Porphyrins • Cyclic compounds that bind metal ions • Chlorphyll (Mg2+) • Central to solar energy utilization • Heme (Fe2+) • Most prevalent metalloporphyrin in humans • Central to oxygen sensing and utilization • Cobalamin (Cobalt)
- 4. PORPHYRINS HC HC N H CH CH Pyrrole ring •Porphyrin: Cyclic molecule formed by linkage of four pyrrole rings through methenyl bridges
- 5. Porphyrin Side Chains • M = Methyl (-CH3) • V = Vinyl (-CH=CH2) • P = Propionyl (-CH2-CH2-COO-) • A = Acetyl (-CH2-COO-)
- 6. Heme •One ferrous (Fe2+) atom in the center of the tetrapyrrole ring of Protoporphyrin IX •Prosthetic group for • Hemoglobin and Myoglobin • The Cytochromes • Catalase and Tryptophan pyrrolase • Nitric Oxide Synthase •Turnover of Hemeproteins (Hemoglobin, etc) is coordinated with synthesis and degradation of porphyrins •Bound iron is recycled
- 7. Heme Protoporphyrin III prefix or suffix r ing substituents between rings uro- acetate, propionate - - copro- methyl, propionate - - proto- methyl, propionate, vinyl -porphyrinog e n - - methylene -porphyrin - - methene
- 8. Biosynthesis of Heme •Synthesized in every human cell •Liver (15%): •Bone Marrow (80%)
- 9. COOH CH2 CH2 COSCoA CH2 NH2 COOH SUCCINYL CoA GLYCINE All Carbon and Nitrogen atoms provided by 2 building blocks:
- 10. COOH CH2 CH2 COSCoA CH2 NH2 COOH SUCCINYL CoA GLYCINE is Decarboxylated IN MITOCHONDRIA AMINOLEVULINIC ACID SYNTHASE - CO2
- 11. COOH CH2 CH2 C=O CH2 NH2 Condense to form: AMINOLEVULINIC ACID (ALA) MOVES OUT OF THE MITOCHONDRION
- 12. COOH CH2 CH2 C=O CH2 NH2 COOH CH2 CH2 C=O CH2 NH2 2 Molecules dehydrated by ALA DEHYDRATASE -2 H2O
- 17. HYDROXYMETHYLBILANE SYNTHASE & UROPORPHYRINOGEN III SYNTHASE •Four PBG molecules condense •Ring closure •Isomerization
- 20. SERIES OF DECARBOXYLATIONS & OXIDATIONS • Porphyrinogens: • Chemically reduced • Colorless intermediates • Porphyrins: • Intensely colored • Fluorescent • Uroporphyrinogen III • Coproporphyrinogen III Moves back into Mitochondrion • Protoporphyrinogen IX • Protoporphyrin IX
- 22. HEME Fe2+ chelated by Protoporphyrin IX Assisted by Ferrochelatase CH3-
- 24. Regulation of Heme Synthesis
- 25. AMINOLEVULINIC ACID SYNTHASE • Two tissue-specific isozymes • Coded on separate genes • In Liver, heme represses synthesis and activity of ALAS • Heme can be used for treatment of acute porphyric attack • In RBC heme synthesis regulation is more complex • Coordinated with globin synthesis
- 26. COOH CH2 CH2 COSCoA CH2 NH2 COOH SUCCINYL CoA GLYCINE IN MITOCHONDRIA AMINOLEVULINIC ACID SYNTHASE RATE-CONTROLLING STEP IN HEPATIC HEME SYNTHESIS COOH CH2 CH2 C=O CH2 NH2 ALA
- 28. Disorders of Heme Synthesis • Acquired: Lead poisoning • Congenital: Porphyrias • Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.)
- 29. LEAD TOXICITY Symptoms Irritibility Poor appetite Lethargy Abdominal pain (with or Sleeplessness without vomiting) Headaches Constipation Pathophysoiology Binds to any compound with a sulfhydryl group Inhibits multiple enzyme reactions including those involved in heme biosynthesis (ALA dehydratase & ferrochelatase)
- 30. COOH CH2 CH2 C=O CH2 NH2 COOH CH2 CH2 C=O CH2 NH2 -2 H2O ALA moves out of the mitochondrion ALA DEHYDRATASE Inhibited by Heavy Metal: LEAD POISONING PBG N H CH2 NH2 A P
- 31. Lead Poisoning
- 32. Lead Poisoning ALAD and Ferrochelatase Are particularly sensitive to Lead inhibition Lead Poisoning Fe + PPIX Ferrochelatase Heme
- 33. Disorders of Heme synthesis • Porphyrias are group of inborn errors of metabolism associated with the biosynthesis of heme.(Greek ‘porphyria’ means purple). • These are characterised by increased production and production and excretion of porphyrins and/or their precursors (ALA + PBG). • Many of the porphyrias are inherited as autosomal dominant traits.
- 34. • Porphyrias may be broadly grouped into 3 types: a. Hepatic porphyrias b. Erythropoietic porphyrias c. porphyrias with both erythropoietic and hepatic abnormalities.
- 36. PORPHYRIAS A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway The majority of the porphyrias are inherited in a autosomal dominant fashion - thus, affected individuals have 50% normal levels of the enzymes, and can still synthesize some heme Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations Attacks of the disease are triggered by certain drugs, chemicals, and foods, and also by exposure to sun Treatment involves administration of hemin, which provides negative feedback for the heme biosynthetic pathway, and therefore, prevents accumulation of heme precursors
- 37. ACUTE INTERMITTENT PORPHYRIA Hepatic, autosomal dominant Caused by a deficiency in porphobilinogen deaminase, which is involved in the conversion of porphobilinogen (PBG) to uroporphyrinogen III PBG, uroprophryin, and 5-ALA accumulate in the plasma and the urine Patients have neuropyschiatric symptoms and abdominal pain (neurovisceral)
- 39. PORPHYRIA CUTANEA TARDA Most common porphyria Hepatic, autosomal dominant Disease is caused by a deficiency in uroporphyrinogen decarboxylase, which is involved in the conversion of uroporphyrinogen III to coproporphyrinogen III Uroporphyrinogen accumulates in urine Patients are photosensitive (cutaneous photosensitivity) Accumulation of porphyrinogens results in their conversion to porphyrins by light Porphyrins react with molecular oxygen to form oxygen radicals Oxygen radicals can cause severe damage to the skin
- 43. BLOOD CELLS LIVER Bilirubin diglucuronide (water-soluble) 2 UDP-glucuronic acid via bile duct to intestines Urobilinogen formed by bacteria KIDNEY CO Biliverdin Heme oxygenase O2 Bilirubin (water-insoluble) NADP+ NADPH Biliverdin reductase Heme Globin Hemoglobin reabsorbed into blood Bilirubin (water-insoluble) via blood to the liver INTESTINE
- 44. Disorder of Hb catabolism •Disease or conditions that interfere with bilirubin metabolism may cause a rise in its serum concentration of bilirubin Total bilirubin 0.1 to 1mg/dl Conjugated 0.1 to 0.4mg/dl Unconjugated 0.2 to 0.7mg/dl NORMAL LEVELS
- 45. Hyperbilirubinaemia • When serum bilirubin exceeds 1mg/dl – HYPERBILIRUBINAEMIA • >2.2 to 5mg/dl - JAUNDICE Yellowish discoloration of skin and sclera due to deposition of bilirubin in the tissues. The condition is called jaundice or icterus
- 46. INCREASED HAEMOLYSIS ↑breakdown of Hb JAUNDICE LIVER DAMAGE ↓Excretion of bilirubin JAUNDICE BILE DUCT OBSTRUCTION ↓Excretion of bilirubin JAUNDICE CAUSES OF JAUNDICE
- 47. JAUNDICES
- 48. NORMAL METABOLISM OF BILE PIGMENTS CELLS OF RES Indirect bilirubin NADP+ NADPH2 Biliverdin reductase Biliverdin Iron Globin Verdoglobin NADP+ Hemoxi- genase NADPH2 Hemoglobin ERYTHROCYTES K I D N E Y S Stercobilinogen URINE Stercobilin Indirect bilirubin 1,7- 20,5 mkmol/l albumin albumin Indirect bilirubin UDP-glucoronil- transferase Direct bilirubin 0.8- 4.3 mkmol/l B L O O D L I V E R Bilirubin mono- glucoronid, 20 % Bilirubin di-glucoronid, 80 % Dipyrols -glucoro- nidase Glucoronic acid Direct bilirubin B I L E I N T E S T I N E Mesobilirubin Mesobilirubin (urobilinogen) Stercobilinogen Stercobilin STOOL
- 49. METABOLISM OF BILE PIGMENTS IN HEMOLYTIC JAUNDICE CELLS OF RES Indirect bilirubin Indirect bilirubin albumin albumin Indirect bilirubin Biliverdin reductase UDP-glucoronil- transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin NADP+ NADPH2 Hemoglobin Hemoxi- genase B L O O D L I V E R Bilirubin mono- glucoronid, 20 % Bilirubin diglucoronid, 80 % -glucoro- nidase Glucoronic acid Direct bilirubin B I L E ERYTHROCYTES K I D N E Y S I N T E S T I N E STOOL Stool hypercholic URINE Urine dark Mesobilirubin Mesobilinogen (urobilinogen) Stercobilinogen Stercobilin Stercobilinogen StercobilinUrobilin
- 50. METABOLISM OF BILE PIGMENTS IN HEPATIC JAUNDICE CELLS OF RES Indirect bilirubin Indirect bilirubin albumin albumin Indirect bilirubin Biliverdin reductase UDP-glucoronil- transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin NADP+ NADPH2 Hemoglobin Hemoxi- genase B L O O D L I V E R Bilirubin mono- glucoronid, 20 % Bilirubin diglucoronid, 80 % -glucoro- nidase Glucoronic acid Direct bilirubin B I L E ERYTHROCYTES K I D N E Y S Urobilinogen I N T E S T I N E STOOL Stool hypocholic URINE Urine dark Stercobi- linogen StercobilinBilirubinUrobilin Mesobilirubin Mesobilinogen (urobilinogen) Stercobilinogen Stercobilin
- 51. METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE JAUNDICE CELLS OF RES Indirect bilirubin Indirect bilirubin albumin albumin Indirect bilirubin Biliverdin reductase UDP-glucoronil- transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin NADP+ NADPH2 Hemoglobin Hemoxi- genase B L O O D L I V E R Bilirubin mono- glucoronid, 20 % Bilirubin diglucoronid, 80 % Bile acids -glucoro- nidase Glucoronic acid Direct bilirubin B I L E Direct bilirubin ERYTHROCYTES K I D N E Y S Direct bilirubin I N T E S T I N E STOOL Stool acholic, steatorhea URINE Direct bilirubin Bile acids Urine dark, foaming