IRON METABOLISM

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PowerPoint Presentation: 

IRON METABOLISM Dr. Prabesh K Choudhary 2 nd Yr, Path NAMS

Summary: 

Summary Overview Iron distribution Iron storage Iron absorption Molecular regulation of iron metabolism

An Overview of Iron Metabolism: 

An Overview of Iron Metabolism Gut Blood Cells Low pH of stomach solubilizes Fe-containing ionic compounds. Fe transporters facilitate absorption into blood stream Fe 3+ ions are bound and chelated by Transferrin (Tf). Transferrin transports Fe to tissues Maintains solubility Keeps Fe ions unreactive Transferrin endocytosis is receptor-mediated (TfR) Endocytosis results in Fe 3+ release Fe is distributed to topologically distinct regions of the cell via Fe transporter and/or channels Usage: Protein components (Heme) Storage: Ferritin (Fe 3+ ) Toxicity

Iron: 

Iron Element (Fe) Molecular weight 56 May be 2+ or 3+ Ferrous (2+) “reduced” - gained an electron Ferric (3+) “oxidised” - lost an electron Fe +++ + e -  Fe ++ Redox states allows activity passing electrons around body Redox change required for iron metabolism

Distribution of iron: 

Distribution of iron

Haemoglobin: 

Haemoglobin 0.34% iron by weight 2g in men & 1.5g in women 1ml of packed RBCs> 1mg

PowerPoint Presentation: 

STRUCTURE OF HEME

Storage compartment: 

Storage compartment Ferritin: water soluble Hemosiderin: water insoluble Apoferritin: 24 subunits arranged in 12 dimers forming a dodecahdron> sphere Apoferritin monomers: H & L chain types L-monomers: 15 hydrophilic residues; binds iron & promotes it’s retention

Storage compartment: 

Storage compartment H-monomers: fewer hydrophilic residues; contributes iron-binding histidyl to the intermonomeric pore (Iron exit & enter point) H-monomers also have ferroxidase activity enabling apoferritin to take up or release iron rapidly Apoferritin rich with H-monomers>takes up iron more readily but retains it less avidly Liver & spleen: rich in L-monomers

Human “Isoferritins”: 

Human “Isoferritins”

Storage compartment; contd.: 

Storage compartment; contd. Plasma ferritin roughly corresponds with total iron stores Adult male: 800-1000mg Hemosiderin: predominantly found in macrophages; contain 25-30% iron by weight

Myoglobulin: 

Myoglobulin Structure> similar to hemoglobin; monomeric Each molecule consists of a heme group and surrounded by loops of long polypeptide chain Present in small amount in skeletal & cardiac muscle cells; function as O2 reservoir Labile iron pool: 80-90mg Tissue iron compartment: cytochromes & iron containing enzymes; 6-8mg; very sensitive to iron deficiency

Transport compartment; transferrin: 

Transport compartment; transferrin Smallest(3mg) but most active Normal turn over: 10 times each day 2 binding sites for Fe+++; bilobed each containing N & C domains Normally 1/3 rd of iron binding sites occupied by iron Plasma transferrin: 200mg/dl carrying 100micro gram of iron Synthesized by hepatocytes & monocyte-macrophage

Dietary iron: 

Dietary iron Average daily iron intake: 10-20mg Daily iron loss in stool: 1mg

Bioavailability of iron: 

Bioavailability of iron Inhibitors:oxalates, phytates, tannates & phosphates Promoters: hydroquinone, ascorbate, lactate, pyruvate, succinate, fructose, cysteine & sorbitol ( reducing substances ) Red wine>>inhibitor Fe2+ better absorbed than Fe+3 Amino-acids, keto-sugars & mucins in gastric juice prevents iron precipitation as OH

Transport across duodenum: 

Transport across duodenum Haem iron - carrier protein (endocytosis) Fe3+ - attachment to an integrin. Fe2+ - intestinal transporter DMT1

Transport across duodenum: 

Transport across duodenum

Iron exporters: 

Iron exporters Transporting iron from basolateral membrane of enterocytes to circulation; from macrophage in to circulation for formation of new Hb. Ferroportin. Hephaestin.

Ferroportin: 

Ferroportin Ferroportin-1 in basal portion of placental syncytiotrophoblasts, basolateral surface of duodenal enterocytes, macrophages, hepatocytes. Upregulated by amount of available iron, downregulated through interaction with hepcidin.

Haephaestin: 

Haephaestin Mutation in mice with sex-linked anaemia – enterocytes are iron loaded. Homology to ceruloplasmin. Link between iron deficiency and copper deficiency – administration of copper facilitates egress of iron from tissue(s) into circulation.

Maintainence of Iron homeostasis: 

Maintainence of Iron homeostasis Concept of “mucosal block”: administration of a dose of iron prevents any further absorption Mucosal intelligence: close relation between iron need & iron dose , on one hand & amount of iron absorbed on the other hand

PowerPoint Presentation: 

Protein Function Expression Ft (H and L subunits) ( IREs 5’ UTR ) Iron storage Most cells TfR1 ( IREs 3’ UTR ) Iron uptake Erythroid cells, epithelial cells rapidly growing (intestinal crypt cells). Other cells including macrophages TfR2 Iron uptake Hepatocyte, circulating monocytes DMT1 Iron import; iron release from endosome to cytoplasm Brush border of epithelial cell of the intestinal villus. Endodomal vesicles in erythroid cells and other cell types FP1 ( IREs 5’ UTR ) Iron export Basolateral membrane of epithelial cell of the intestinal villus; placenta; other cell types

PowerPoint Presentation: 

Protein, carriers, & “regulators” in iron metabolism Protein Function Expression Duodenal cytochrome b Ferric reductase Brush border of enterocytes of the intestinal villus. Hephaestin Ferroxidase Basolateral membrane and vesicles of enterocytes of the intestinal villus. HFE (No IREs) Interacts with TfR1 Intestinal crypt cells and tissue macrophages Hepcidin (No IREs) Antibacterial activity; iron homeostasis? Liver; blood; urine IRP1 AND IRP2 Posttranscriptional control of target mRNAs (Ft, TfR1, DMT1, FP1/IR1/MTP1, mitochondrial aconitase, erythroid aminolevulinate synthase) Mainly: Liver, spleen, kidney, heart. Also: duodenum, brain

Effect of mutation of specific proteins: 

Effect of mutation of specific proteins Iron overload Iron deficiency Hypotransferrinaemia - recessive HFE gene mutation TfR2 gene mutation – recessive Ferroportin mutation – autosomal dominant Hepcidin mutations Hemojuvelin mutations H ferritin mutation - dominant TMPRSS6 mutation – IRIDA >>normally produce type 2 transmembrane serine protease>> upregulation of hepcidin

Hepcidin, primary regulator: 

Hepcidin, primary regulator Antimicrobial peptide; 20-25 amino acids Chromosome 19, synthesized by hepatocyes. Associated with HFE signalling pathway Increased expression decreased iron absorption and release Mutation: hemochromatosis Increased expression: iron deficiency Hepcidin mRNA expression increased by erythropoetin, hypoxia & inflammation *Exception: HFE mutation* Also binds ferroportin and causes internalization & proteolysis

Regulation of hepcidin: 

Regulation of hepcidin

Hepcidin regulation by BMPs: 

Hepcidin regulation by BMPs BMP - members of TGF-b superfamily which regulate cell proliferation, differentiation, apoptosis. BMP receptors: type I and II>>phosphorylation of cytoplasmic R-Smads. R-Smads associate with Smad4>> translocate to nucleus>> transcription of target genes ( hepcidin ). BMP’s effect on cellular response also modulated by BMP coreceptors. Hemojuvelin (HJV) - iron-specific, stimulates BMP2/4 pathway. Disruptive mutation>>juvenile hemochromatosis 1. GPI linked membrane form - stimulates BMP signalling and hepcidin expression. 2. Soluble HJV (sHJV) - antagonist of BMP signalling.

Hepcidin regulation by iron: 

Hepcidin regulation by iron Production stimulated by increased plasma iron and tissue stores. Negative feedback - hepcidin decreases release of iron into plasma (from macrophages and enterocytes). Fe-Tf increases hepcidin mRNA production (dose dependent relationship).

Hepcidin regulation by iron-iron sensors: 

Hepcidin regulation by iron-iron sensors HFE interacts with TfR1, but dissociates when Fe-Tf binds to TfR1. Amount of free HFE proportional to Tf-Fe. TfR2 – Tf-Fe stabilises TfR2 protein in dose dependent fashion. Fe-Tf binding increases fraction of TfR2 localizing to recycling endosomes, decreases fraction of TfR2 localizing to late endosomes where it is targeted for degradation. TfR2 competes with TfR1 for binding to HFE. HFE-TfR2 may regulate hepcidin expression by promoting HJV/BMP signalling, impacting upon hepcidin expression.

Transport of iron; transferrin: 

Transport of iron; transferrin Encoded on long arm of chromosome 3. Half life 8 days. Hepatic synthesis. Complete lack incompatible with life (hypotransferrinaemia).

Tranferrin receptor: 

Tranferrin receptor Also on long arm of chromosome 3. homodimeric transmembrane protein. Found in most cells. Most dense on erythroid precursors, hepatocytes & placental cells. Restricted expression: both TfR1 and TfR2 present at high levels in hepatocytes, epithelial cells of small intestine including duodenal crypt cells.

Transport of iron: 

Transport of iron

Transport of iron: 

Transport of iron

Iron within the erythrocytes: 

Iron within the erythrocytes Either transported into the mitochondria or taken up by ferritin within siderosomes. Impaired heme synthesis (Lead poisoning & sideroblastic anemia)>>accumulation of iron into the mitochondria>>siderotic granules>> ringed sideroblast Siderotic granules (ferritin aggregates) normally demonstrable in cytoplasm in small amount & located in lysosomal organelles designated as siderosomes>>sideroblast (20-50% of erythroid precurssor)

Intracellular regulation of iron metabolism: 

Intracellular regulation of iron metabolism Synthesis of apoferritin,TfR,d-ALA synthase,apotransferrin,aconitase,DMT-1 & ferroportin is regulated posttrancriptionally mRNA of these proteins contain 1 or more iron responsive elements (IREs) IRE located at 5’ end>> regulate translation IRE located at 3’ end>> regulate stability of mRNA IRE has a stem & loop structure, loop consisting of nucleotide sequence of CAGUGC

Intracellular regulation of iron metabolism: 

Intracellular regulation of iron metabolism IRE in apoferritin mRNA: 5’UTR region(1) IRE in TfR mRNA: 3’UTR region (5) Iron regulatory proteins-1(IRP-1): cytoplasmic acotinase IRP-2:lack of acotinase activity Absence of Fe>IRP-1 binds IREs>Fe absortion IRP-2: proteolyzed in presence of Fe NO increases binding of IRP-1 to IREs & enhances degradation of IRP-2 IRP-3’IRE>>stabilisation>>translation

Iron-regulatory proteins and iron-responsive element binding protein: 

Iron-regulatory proteins modulate synthesis of TfR, ferritin, DMT1. IRP1 and IRP2 – cytosolic RNA binding proteins. Bind to iron-responsive elements located in 5’ or 3’ untranslated regions of specific mRNAs encoding ferritin, TfR, DMT1 and (in erythroid cells) dALAS. Iron-regulatory proteins and iron-responsive element binding protein

IRPs and IRE-BP: 

Binding of IRPs to IREs at 5’ end of transcripts of e.g. Ferritin, dALAS – decreases rate of synthesis; binding to 3’ end of transcripts e.g. TfR or DMT1, mRNA half life prolonged, increased synthesis. IRE-IRP complex senses state of iron balance – conformational change. IRPs and IRE-BP

IRP-IRE-BP: 

End result – in iron overload, increased ferritin (for adequate storage), decreased TfR (minimise further iron entry into cell), and vice versa in iron deficiency. IRP-IRE-BP

Summary: 

Summary Overview Iron distribution Iron storage Iron absorption Molecular regulation of iron metabolism