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PORPHYRIN AND HEME METABOLISM

PORPHYRIN AND HEME METABOLISM. Porphyrins metal and protein Hemoproteins Heme Hemoglobin Iron Globin chains Protoporphyrin III (IX). PORPHYRINS. NOMENCLATURE Types of substituents Symmetry I or III Oxidation between rings Methylene -CH2- Methene -CH=. Heme Fig.44.2 Page 836.

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PORPHYRIN AND HEME METABOLISM

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  1. PORPHYRIN AND HEME METABOLISM • Porphyrins metal and protein • Hemoproteins • Heme • Hemoglobin • Iron • Globin chains • Protoporphyrin III (IX)

  2. PORPHYRINS • NOMENCLATURE • Types of substituents • Symmetry I or III • Oxidation between rings • Methylene -CH2- • Methene -CH=

  3. Heme Fig.44.2 Page 836 Protoporphyrin III

  4. Reactions forProtoporphyrin IXFig. 44.3Page 837

  5. Step 1 Synthesis of d-amino levulinic acid Fig. 44.4 837 Mitochondrial location Rate limiting Pyridoxal phosphate (decarboxylase) Regulation of enzyme levels by iron and protohemin

  6. Step 2 Synthesis of porphobilinogen Fig. 44.5 Page 838 Also called porphobilinogen synthase Zinc-dependent Site of lead toxicity

  7. Further Reactions • Step 3 Tetrapyrrole formation • synthesis of hydroxymethylbilane • synthesis of uroporphyrinogen III • Step 4 Conversion to protoporphyrin III • uro to copro • copro to proto • porphyrinogen to porphyrin • Step 5 Protoheme synthesis • insertion of ferrous iron • site of lead toxicity

  8. 1 2 3 3 4 4 5

  9. Protohemin formation -- formation of superoxide Heme Proteins Protoheme (or heme) + globin ~ hemoglobin Variations in heme Fe ligands 4, 5, or 6 Ferrous or Ferric Protoporphyrin III attachment to protein

  10. Heme b Heme c Heme a

  11. Iron-IRE

  12. Porphyrias Treatment Hematin (hemin hydroxide)

  13. 1 2 3 3 4 4 5

  14. Heme DegradationFig. 44.7Page 839

  15. ReactionsFig. 44.8Page 840

  16. Heme oxygenase Biliverdin reductase Serum albumin GSH S-transferase Bilirubin UDP-glucuronyl transferase Spleen Macrophages Blood Liver

  17. Features Reactions Jaundice hemolytic obstructive Neonate kernicterus liver disease Gilbert’s disease Heme Degradation • Blood Proteins • serum albumin • haptoglobin • hemopexin

  18. Blood So Far • Plasma • Erythrocyte • Hemoglobin • Globin chains • Protoporphyrin III • Iron

  19. Iron Balance

  20. IRON METABOLISM Fig. 44.6 Page 838

  21. Iron Absorption • Low but regulated • Ferrous iron conversion needed • Heme iron by separate pathway • Reducing agents aid uptake-vitamin C • Factors in breast milk facilitate uptake (lactoferrin)

  22. Promoters: Ascorbic acid Meat Citric Acid Some spices -carotene Alcohol Inhibitors: Phytic acid Polyphenols Tannins Calcium Promoters and inhibitors of non-heme iron absorption Adapated from Paul Sharp Kings College UK

  23. ferritin Dcytb DRA Fe3+ Fe3+ Fe3+ Tf e- Fe2+ DMT1 e- LIP Hp Fe2+ IREG1 HO HCP1 Duodenal iron transport Fe3+ Fe2+ heme Plasma Gut lumen Adapated from Paul Sharp Kings College UK

  24. Hepcidin Master Regulator • Liver-produced antimicrobial peptide • Lowers iron absorption by binding to ferroportin, resulting in internalization, and degradation • Expression is COMPLEX and related to liver iron mediated by TfR2 (Iron induces). • Expression increased by IL6

  25. Iron transport Steap3

  26. Iron Storage • Ferritin • Serum ferritin • Hemosiderin

  27. Iron Utilization • Heme synthesis • Non-heme iron proteins • Iron mobilization is dependent on copper ferroxidases

  28. Iron Mobilization

  29. TfR and Ferritin Posttranscription RegulationFig. 16.21 16.22Page 290 Additional IRE containing mRNA transcripts Include : DMT1 ALA synthase Ferroportin Others

  30. Iron Imbalance • Excretion • Deficiency • Toxicity • Hemochromatosis • Seconday effects (genetic and environmental)

  31. Dcytb Steap 2 DMT1 Ferritin Ferroportin Hephaestin Heme Carrier Protein1 Heme Oxygenase Transferrin Hepcidin HFE (b-microglobulin) (transferrin receptor)

  32. Nutritional Issues-Iron • Deficiency • Causes • Diagnosis • Consequences • Supplementation • Toxicity

  33. Causes of Iron deficiency • Pathological blood loss - hookworm • Low bioavailability of iron in food • Infection: more prevalent in developing countries 58% of females in Asia vs 10% of Western females are iron deficient • Being female • Pregnancy • Adapated from Paul Sharp Kings College UK

  34. Consequences of Iron Deficiency • Poor pregnancy outcomes • Increased perinatal morbidity • Defective psychomotor development • Impaired educational performance • Impaired work capacity • Adapated from Paul Sharp Kings College UK

  35. Adapated from Paul Sharp Kings College UK

  36. Micronutrients-Iron • Dietary Recommended Intakes (DRI) • RDAs are gender specific • UL = 40 mg

  37. Iron Absorption Adapts 24 Post Delivery Weeks of Gestation Barrett et al., 1994

  38. Micronutrients-Iron • Food Sources • Toxicity Concerns • Supplementation Needed?

  39. Supplements Necessary?

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