Iron Metabolism PDF

Iron Metabolism Objectives: Role of Iron Iron Metabolism Abnormal Iron Metabolism HUMAN IRON METABOLISM 3  HUMAN IRON METABOLISM  Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron  Iron is an essential element...

Iron Metabolism Objectives: Role of Iron Iron Metabolism Abnormal Iron Metabolism HUMAN IRON METABOLISM 3  HUMAN IRON METABOLISM  Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron  Iron is an essential element for most life on earth, including human beings 4  HUMAN IRON METABOLISM  The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease 5  HUMAN IRON METABOLISM  Hematologists have been especially interested in the system of iron metabolism because iron is essential to red blood cells  Most of the human body's iron is contained in RBCs' hemoglobin, and iron deficiency is the most common cause of anemia 6 HUMAN IRON METABOLISM Understanding this system is also important for understanding diseases of iron overload Recent discoveries in the field have shed new light on how humans control the level of iron in their bodies and created new understanding of the mechanisms of several diseases 7 HUMAN IRON METABOLISM  Human beings use 20 mg of iron each day for the production of new red blood cells, much of which is recycled from old red blood cells 8  ROLE OF IRON IN THE BODY Iron have several vital functions  Carrier of oxygen from lung to tissues  Transport of electrons within cells  Co-factor of essential enzymatic reactions: Neurotransmission Synthesis of steroid hormones Synthesis of bile salts Detoxification processes in the liver  IRON EXISTANCE 1. Heme Iron:  hemoglobin, myoglobin, cytochrom-c oxidase, catalase 2. Non-heme iron:  Fe-S complexes (xanthine oxidase), DNA synthesis (ribonucleotide reductase)  ABSORBING IRON FROM THE DIET 11 Dietary iron in the form of non-heme iron or heme iron is absorbed in the duodenum  Where DMT1=== divalent metal transporter 1 DCYTB===duodenal cytochrome b HCP1===heme carrier protein 1  ABSORBING IRON FROM THE DIET  Like most mineral nutrients, iron from digested food or supplements is almost entirely absorbed in the duodenum by enterocytes of the duodenal lining  These cells have special molecules that allow them to move iron into the body  To be absorbed, dietary iron must be in its ferrous Fe2+ form 14  ABSORBING IRON FROM THE DIET CONT’D  A ferric reductase on the enterocytes' brush border, duodenal cytochrome b (Dcyt b) which reduces ferric Fe3+ to Fe2+  A protein called divalent metal transporter 1 (DMT1), which transports all kinds of divalent metals into the body, then transports the iron across the enterocyte's cell membrane and into the cell 15  ABSORBING IRON FROM THE DIET  These intestinal lining cells can then either:  Store the iron as ferritin (in which case the iron will leave the body when the cell dies and is sloughed off into feces) or  The cell can move it into the body, using a protein called ferroportin 16 FERRITIN STRUCTURE 17  ABSORBING IRON FROM THE DIET CONT’D  The body regulates iron levels by regulating each of these steps  For instance, cells produce more Dcyt b, DMT1 and ferroportin in response to iron deficiency anemia 18  ABSORBING IRON FROM THE DIET  Our bodies' rates of iron absorption appear to respond to a variety of interdependent factors:  Total iron stores  The extent to which the bone marrow is producing new red blood cells  The concentration of hemoglobin in the blood  The oxygen content of the blood 19  ABSORBING IRON FROM THE DIET  We also absorb less iron during times of inflammation  Recent discoveries demonstrate that hepcidin regulation of ferroportin is responsible for the syndrome of anemia of chronic disease 20  ABSORBING IRON FROM THE DIET  While Dcyt b and DMT1 are unique to iron transport across the duodenum, ferroportin is distributed throughout the body on all cells which store iron  Thus, regulation of ferroportin is the body's main way of regulating the amount of iron in circulation 21 Regulation of Iron Homeostasis  HOW HEPCIDIN REGULATES IRON Spleen Hepcidin Liver Fpn Fpn Plasma Fe-Tf Fpn Bone marrow and other sites of iron usage Duodenum Nemeth E, et al. Science. 2004;306:2090-2093. Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.  FACTORS AFFECTING IRON ABSORPTION  Most of dietary iron is present in the Fe3+ state either as ferric hydroxide or ferric organic compounds, its absorption is affected by : 1 Gastric HCl: 2. Reducing substances: e.g., cysteine (SH), ascorbic acid and glutathione 3. Body needs 4. A high phosphate diet 5. Phytic acid (of cereals) and oxalate 6. Steatorrhea:  HOW CELLS GET THEIR IRON FROM THE BODY 26  HOW CELLS GET THEIR IRON FROM THE BODY  Most of the iron in the body is located on hemoglobin molecules of RBCs  When RBCs reach a certain age, they are degraded and engulfed by specialized scavenging macrophages 27  HOW CELLS GET THEIR IRON FROM THE BODY  These cells internalize the iron-containing hemoglobin, degrade it, put the iron onto transferrin (Apo-Tf) molecules, and then export the transferrin-iron (Fe2-Tf) complexes back out into the blood  Most of the iron used for blood cell production comes from this cycle of hemoglobin recycling 28 HOW CELLS GET THEIR IRON FROM THE BODY 29  HOW CELLS GET THEIR IRON FROM THE BODY  All cells use some iron, and must get it from the circulating blood  Since iron is tightly bound to transferrin, cells throughout the body have receptors (TfR) for Fe2-Tf complexes on their surfaces  These receptors engulf and internalize both the protein and the iron attached to it 30  HOW CELLS GET THEIR IRON FROM THE BODY  Once inside, the cell releases the iron from Fe2-Tf-Tf-R complexes by proton-pump mechanism  The cell transfers the iron to ferritin, the internal iron storage molecule, via ferrous-iron transporter (DMT1)  Cells have advanced mechanisms for sensing their own need for iron 31  TRANSFERRIN STRUCTURE  Transferrin (Tf) is glycoprotein with two high affinity binding sites for Fe3+  Tf transports Fe between sites of absorption, storage and utilization  Cells (esp. Erythroid precursors) strip Fe from Tf by expressing Tf-R  Tf synthesis is stimulated by lack of Fe in the body 32 TRANSFERRIN STRUCTURE 33  TRANSFERRIN STRUCTURE  Transferrin's primary protein structure is made up of about 700 amino acids (80 kDa)  Transferrin has a combination of -helices and -sheets to form two different lobes: N- and C- terminus 34  TRANSFERRIN STRUCTURE  These two domains are held together by a short peptide and create a deep hyrophobic site  The amino acids that bind the ferric iron ion are the same for both lobes:  Two tyrosine residues, one aspartate, and one histotine 35  TRANSFERRIN STRUCTURE  The binding of iron also needs an anion which is usually carbonate (CO32-)  The three- charge, contributed by the two tyrosine and one aspartate, balances the 3+ charge of ferric iron 36 TRANSFERRIN STRUCTURE 37  TRANSFERRIN STRUCTURE  The charge on the anion is balanced by the adjacent positive charge on the protein (in transferrins, this postive charge comes from the arginine side chain and the N- termins of an -helix) 38 TRANSFERRIN RECEPTOR 39  TRANSFERRIN RECEPTOR  The transferrin receptor is a transmembrane homodimer consisting of two identical monomers  These monomers are able to bind up to two molecules of transferrin  The monomers are joined by two disulfind bonds at Cys89 and Cys89 40  TRANSFERRIN RECEPTOR  This structure contains a short NH2 terminal cytoplasmic region (residues 1 to 67), a single transmembrane pass (residues 68 to 88), and a large extracellular ectodomain (residues 89 to 760)  The extracellular portion bears a trypsin-sensitive region and contains a binding site for transferrin 41  TRANSFERRIN RECEPTOR  The transferrin receptor is butterfly-like in shape with three distinct domains  Apical  Protease-like  Helical  The membrane stalk probably involves disulfide bonded residues 42  BODY IRON STORES 43 BODY IRON STORES  1918 illustration of blood cell production in the bone marrow  In iron deficiency, the bone marrow produces fewer blood cells, and as the deficiency gets worse, the cells become smaller 44  BODY IRON STORES  Most well-nourished people in industrialized countries have 3-4 grams of iron in their bodies  Of this, about 2.5 g is contained in the hemoglobin needed to carry oxygen through the blood 45  BODY IRON STORES  Another 400 mg is devoted to cellular proteins that use iron for important cellular processes like storing oxygen (myoglobin), or performing energy-producing redox reactions (cytochromes)  3-4 mg circulates through the plasma, bound to transferrin (Fe2-Tf) 46  BODY IRON STORES  Iron-deficient people will suffer or die from organ damage well before cells run out of the iron needed for intracellular processes like electron transport  Most stored iron is bound by ferritin molecules; the largest amount of ferritin-bound iron is found in cells of the liver hepatocytes, the bone marrow and the spleen 47  BODY IRON STORES  The liver's stores of ferritin are the primary source of reserve iron in the body  Macrophages of the reticuloendothelial system store iron as part of the process of breaking down and processing hemoglobin from engulfed red blood cells 48  BODY IRON STORES  Iron is also stored as a pigment called hemosiderin in an apparently pathologic process  This molecule appears to be mainly the result of cell damage  It is often found engulfed by macrophages that are scavenging regions of damage 49  BODY IRON STORES  It can also be found among people with iron overload due to frequent blood cell destruction and transfusions  Men tend to have more stored iron than women, particularly women who must use their stores to compensate for iron lost through menstruation, pregnancy or lactation 50  REASONS FOR IRON DEFICIENCY 51  REASONS FOR IRON DEFICIENCY  Increased demand for iron, which the diet cannot accommodate  Increased loss of iron (usually through loss of blood)  Nutritional deficiency  This can either be the result of failure to eat iron-containing foods, or eating a diet heavy in food that reduces the absorption of iron, or both 52  REASONS FOR IRON DEFICIENCY  Inability to absorb iron because of damage to the intestinal lining  Examples of causes of this kind of damage include:  Surgery involving the duodenum, or  Diseases like Crohn's or  Celiac sprue which severely reduce the surface area available for absorption 53  REASONS FOR IRON DEFICIENCY  Inflammation leading to hepcidin-induced restriction on iron release from enterocytes 54  IRON OVERLOAD 55  IRON OVERLOAD  The body is able to substantially reduce the amount of iron it absorbs across the mucosa  It does not seem to be able to entirely shut down the iron transport process 56  IRON OVERLOAD  In situations where excess iron damages the intestinal lining itself (for instance, when children eat a large quantity of iron tablets produced for adult consumption), even more iron can enter the bloodstream and cause a potentially deadly syndrome of iron intoxication 57  IRON OVERLOAD  Large amounts of free iron in the circulation will cause damage to critical cells in the liver, the heart and other metabolically active organs  Iron toxicity results when the amount of circulating iron exceeds the amount of transferrin available to bind it, but the body is able to vigorously regulate its iron uptake 58  IRON OVERLOAD  Iron toxicity from ingestion is usually the result of extraordinary circumstances like iron tablet overdose rather than variations in diet  Iron toxicity is usually the result of more chronic iron overload syndromes associated with genetic diseases, repeated transfusions or other causes 59  IRON OVERLOAD  There is no physiological mechanism for the excretion of excess iron!  Causes:  Hemochromatosis: congenital enhancement of iron absorbtion  Hemosiderosis: acquired, e.g. regular blood transfusion (aplastic anemias)  Symptoms (over 28g Fe): diabetes, cirrhosis, hypoadrenalism, slow growth in childhood 60 Iron distribution: Iron Sources:  Meat,liver,Fish,eggs,green vegetables,cereals Iron loss:  Dailyloss 1-2 Mg (cell desquamation, ♀ menstruation, pregnancy, multiple births, lactation ) Recyclation of Iron:  From aged erthrocytes( 20 Mg)  Transferrin receptors on cells Iron deficiency (sideropenia): Causes  inadequate intake, reduced resorption, increased loss Symptoms Reduction of iron stores in liver and bone marrow decrease in the amount of plasma ferritin, decrease in the percentage saturation of serum transferrin ,decrease in the level of Hb, morphological changes of erythrocytes microcytic ,hypochromic anemia (excessive menstrual flow, multiple births, GIT bleeding) Therapy  supplementation Iron overload → hemochromatosis: Causes  genetic - iron uptake regulation (hereditary hemochromatosis)  treatment of patients with hemolytic anemias  excessive ethanol and iron ingestion Symptoms accumulation of iron in the liver, pancreas and heart Therapy  bloodletting, chelating agents Recapitulation : 1.Function of iron (O2 transport, redox reactions , detoxification, cell division) 2. Iron can be toxic 3. Complicated regulation at the level of resorption 4. Iron is important for microorganisms 5. Abnormalities of iron metabolism → diseases Iron metabolism:  1Transport of iron from within intestinal enterocytes to the circulation requires that it be oxidized from the ferrous to the ferric form. This oxidation is catalyzed by which of the following proteins? A. Ceruloplasmin B. Hephaestin C. Ferric reductase D. Ferroportin E. Heme oxygenase 2. An old man in our village developed abdominal colic, muscle pain and fatigue. Following a month hospitalization, acute intermittent porphyria was initially diagnosed based on high level of urinary delta aminolevulinic acid. Subsequently analysis of the patient’s circulating red blood cells revealed that 70% contained elevated level of zinc protoporphyrin and the diagnosis was corrected. The corrected diagnossis most likely to be : A. Iron deficiency B. Lead poisoning C. Protoporphyria D. Barbiturate addiction E. Congenital erythropoietic porphyria 1. Which of the following statements about aminolevulinate synthase (ALA synthase) is correct? A. ALA synthase synthesis decreases in individuals treated with drugs such as barbiturates B. ALA synthase catalyses the rate-limiting reaction in heme degradation. C. ALA synthase catalyses the rate-limiting reaction in heme synthesis D. ALA synthase is decreased in patients with acute intermittent porphyria E. ALA synthase is increased in patients with cutena terda porphyria 2. Which of the following is a product of heme degradation? A. Hemin B. Porphobilinogen C. Protoporphyrin D. Urobilinogen E. uroporphyrinogen III 3.Factors decreasing iron absorption are all, except: A. High fiber and cellulose in diet B. Phytate C. Excess of phosphorous in diet D. Vitamin C E. Tea or coffee consumptions with meal