MODULE 4: HEMOGLOBIN AND IRON ENZYME δ-Aminolevulinic Acid δ-Aminolevulinic Acid Dehydratase Porphobilinogen Deaminase Uroporphyrinogen III Cosynthase Uroporphyrinogen Decarboxylase Coproporphyrinogen Oxidase Protoporphyrinogen Oxidase Ferrochelatase Table 1. Heme Synthesis Enzyme Disorders DISEASE MAJOR SYMPTOMS ACCUMULATION PRODUCTS ALAD Deficiency Porphyria Neurovisceral Urinary ALA Acute Intermittent Porphyria Neurovisceral Urinary ALA and PGB Congenital Erythropoietic Porphyria Photosensitivity Porphyria Cutanea Tarda Hepatoerythropoietic Porphyria Photosensitivity Hereditary Coproporphyria Neurovisceral; Photosensitivity Variegate Porphyria Neurovisceral; Photosensitivity Erythropoietic Protoporphyria Photosensitivity Table 2. Globin Chains NAME Alpha Beta Gamma A Gamma G Delta Epsilon Zeta Theta SYMBOL α β γA γG δ ε ζ ϑ STAGE Early embryogenesis (product of yolk sac erythroblasts) Begins in early embryogenesis; peaks during third trimester and begins to decline just before birth Erythrocyte and Urinary Uro 1 and Copro 1 Urinary Uro 7-c Porphyrin Fecal Isocorpio Urinary ALA PGB Copro Fecal Proto Urinary ALA PGB Copro Fecal Proto Erythrocyte Proto Fecal Proto NUMBER OF AMINO ACIDS 141 146 146 (position 136: alanine) 146 (position 136: glycine) 146 146 141 unknown Table 3. Globin Chains GLOBIN CHAIN INTRAUTERINE Zeta 2 + Epsilon 2 Alpha 2 + Epsilon 2 Zeta 2 + Gamma 2 Alpha 2 + Gamma 2 BIRTH Alpha 2 + Epsilon 2 Alpha 2 + Beta 2 TWO YEARS THROUGH ADULTHOOD Alpha 2 + Gamma 2 Alpha 2 + Delta 2 Alpha 2 + Beta 2 COMPARTMENT Functional Storage Table 4. Iron Compartments in Normal Humans FORM AND ANATOMICAL PERCENT OF TOTAL BODY SITE IRON Hemoglobin iron in the blood ~68 Myoglobin iron in muscles ~10 Peroxidase, catalase, cytochromes, riboflavin ~3 enzymes in all cells Ferritin and hemosiderin mostly in macrophages and ~18 hepatocytes; small amounts in HEMOGLOBIN Gower-1 Gower-2 Portland F (Fetal Hemoglobin) F, 60% to 90% A, 10% to 40% F, 1% to 2% A2, <3.5% A, >95% TYPICAL IRON CONTENT (g) BADONG, BONI, CENIZAL, DE GUZMAN, DE LIMA, DELOS REYES, ESPINOLA, MANGOHIG, PATAG, POSO, SALVADOR 2.400 0.360 0.120 0.667 1 MODULE 4: Hemoglobin and Iron Transport all cells except mature red blood cells Transferrin in plasma <1 PROTEIN Table 5. Iron Compartments in Normal Humans LOCATION Hemochromatosis protein (HFE) Hepatocyte membrane Transferrin receptor 2 Hepatocyte membrane Bone morphogenic protein (BMP) Secreted product of macrophages Bone morphogenic protein receptor (BMPR) Hepatocyte (and other cells) membrane Hemojuvelin (HJV) Hepatocyte membrane Sons of mothers against decapentaplegic (SMAD) Hepatocyte (and other cells) cytoplasm 0.0001 FUNCTION A protein that is bound to transferrin receptor 1 (TfR1) until released by the binding of transferrin to TfR1 A hepatocyte transferrin receptor that is able to bind freed HFE to initiate an internal cell signal for hepcidin production The ligand secreted by macrophages that initiates signal transduction when it binds to its receptor in a cell membrane A common membrane receptor initiating signal transduction, within a cell when its ligand (BMP) binds A coreceptor acting with BMPR for signal transduction, leading to hepcidin production A second messenger of signal transduction activated by BMPR-HJV complex, able to migrate to the nucleus and upregulate hepcidin gene expression BADONG, BONI, CENIZAL, DE GUZMAN, DE LIMA, DELOS REYES, ESPINOLA, MANGOHIG, PATAG, POSO, SALVADOR 2
