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

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

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Heme Fig.44.2 Page 836 Protoporphyrin III

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Reactions for Protoporphyrin IX Fig. 44.3 Page 837

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

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

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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

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1 2 3 3 4 4 5

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

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Heme bHeme cHeme a

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Iron-IRE

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Porphyrias Treatment Hematin (hemin hydroxide)

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1 2 3 3 4 4 5

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Heme Degradation Fig. 44.7 Page 839

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Reactions Fig. 44.8 Page 840

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

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Heme Degradation Features Reactions Jaundice hemolytic obstructive Neonate kernicterus liver disease Gilberts disease Blood Proteins serum albumin haptoglobin hemopexin

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Blood So Far Plasma Erythrocyte Hemoglobin Globin chains Protoporphyrin III Iron

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Iron Balance

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IRON METABOLISM Fig. 44.6 Page 838

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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)

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

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LIP e-e- Fe 3+ ferritin e-e- Tf Fe 3+ Fe 2+ HO DMT1 Fe 2+ Hp IREG1 Fe 2+ Dcytb DRA Fe 3+ Gut lumen Plasma Duodenal iron transport heme HCP1 Adapated from Paul Sharp Kings College UK

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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

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Iron transport Steap3

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Iron Storage Ferritin Serum ferritin Hemosiderin

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

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Iron Mobilization

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

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

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

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Nutritional Issues-Iron Deficiency Causes Diagnosis Consequences Supplementation Toxicity

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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

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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

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

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

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Micronutrients-Iron Food Sources Toxicity Concerns Supplementation Needed?

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Young WomenIronZincCopper EAR, mg86.80.7 Age 14-18 % Below EAR 162616 Age 19-30 % Below EAR 151311

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Supplements Necessary?