inorganic biochemistry of iron metabolism

Inorganic Biochemistry of Iron Metabolism: From Molecular Mechanisms to Clinical Consequences. 2e Robert Crichton Copyright  2001 John Wiley & Sons Ltd ISBNs: 0-471-49223-X (Hardback); 0-470-84579-1 (Electronic) Inorganic Biochemistry of Iron Metabolism Inorganic Biochemistry of Iron Metabolism From Molecular Mechanisms to Clinical Consequences Second Edition Robert Crichton Universit ´ eCatholiquedeLouvain,Belgium With the collaboration of Johan R. Boelaert, Volkmar Braun, Klaus Hantke, Jo J. M. Marx, Manuela Santos and Roberta Ward JOHN WILEY & SONS, LTD Chichester • New York • Weinheim • Brisbane • Singapore • Toronto Copyright  2001 John Wiley & Sons, Ltd Baffins Lane, Chichester, West Sussex PO19 1UD, England National 01243 779777 International (+44) 1243 779777 e-mail (for orders and customer service enquiries): cs-books@wiley.co.uk Visit our Home Page on http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. 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QP535.F4 C75 2001 572  .5174 dc21 2001026202 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library. ISBN 0-471-49223-X Typeset in 10.5/12.5pt Palatino by Laser Words, Chennai, India Printed and bound in Great Britain by Antony Rowe, Chippenham, Wiltshire. This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production. Contents Preface xv 1 Solution Chemistry of Iron in Biological Media 1 1.1 Aqueous Solution Chemistry of Iron 1 1.2 Oxygen Free Radicals 2 1.3 Iron Hydrolysis – A Ubiquitous Phenomenon 6 1.4 Hydrolysis of Iron(III) in Acid Media – Formation of Polynuclear Species 6 1.5 Formation of Precipitates 8 1.5.1 Ageing of Amorphous Ferrihydrite to More-crystalline Products 9 1.6 Biomineralization 11 1.6.1 Magnetite Biomineralization by Magnetotactic Bacteria 11 1.7 References 14 2 The Importance o f Iron for Biological Systems 17 2.1 Introduction 17 2.2 Physical Techniques for the Study of Iron in Biological Systems 20 2.3 Haemoproteins 22 2.3.1 Oxygen Carriers 22 2.3.2 Activators of Molecular Oxygen 25 2.3.3 Electron Transport Proteins 31 vi Contents 2.4 Iron–Sulfur Proteins 34 2.5 Other Iron-containing Proteins 37 2.5.1 Mononuclear Non-haem Iron Enzymes 40 Dioxygenases 40 Hydroxylases 41 a-Ketoacid-dependent Enzymes 42 Isopenicillin N Synthase 43 Superoxide Dismutases 43 2.5.2 Dinuclear Non-haem Iron Enzymes 44 (m-Carboxylato)diiron Proteins 45 2.6 References 48 3 Microbial Iron Uptake 49 3.1 Introduction 49 3.2 Siderophores 51 3.2.1 FhuA-mediated Ferrichrome Transport A cross the Outer Membrane–of E. coli 54 3.2.2 FhuA as an Antibiotic Transporter 58 3.2.3 Transport of Ferrichrome Across the Cytoplasmic Membrane 58 3.2.4 Variety of Fe 3+ Transport Systems in Bacteria 63 3.3 Ferrous Iron Transport Systems 63 3.4 Iron Metabolism 64 3.5 Iron Regulation in Bacteria – the Fur Protein 65 3.5.1 The Fur Regulon 66 3.5.2 Siderophore Biosynthesis and Uptake 66 3.5.3 Iron Metabolism and Oxidative Stress Response 70 3.5.4 Genes Regulated by Fur 71 3.5.5 Virulence-Associated Genes 71 3.5.6 Fur-like Proteins 71 DtxR-like Regulators 72 3.5.7 Regulation by Fe 3+ Siderophores 73 3.5.8 Regulation of Outer Membrane Transporter Synthesis by Phase Variation 74 3.5.9 Iron-related Bacterial Virulence 75 3.6 Acknowledgements 76 3.7 References 76 Contents vii 4 Iron Uptake by Plants and Yeast 83 4.1 Iron Acquisition by Plants 83 4.1.1 Introduction 83 4.1.2 Iron Acquisition by the Roots of Plants 84 Dicotyledons and Non-grass Monocotyledons (Strategy I) – Ferrous Iron Transport 84 Graminaceous Plants (Strategy – Ferric Iron Transport 88 Mutants Affected in Iron Transport 90 4.2 Plant Ferritins 91 4.2.1 Developmental Regulation of Ferritin Synthesis 91 4.2.2 Iron-regulated Expression of Ferritin Genes 92 4.3 Iron Acquisition by Yeast 92 4.3.1 Introduction – Pathways for Iron Uptake 93 4.3.2 Cell Surface Reductases 93 4.3.3 Iron Uptake Across the Plasma Membrane 94 Low Affinity Iron-Transport System 94 High Affinity Iron-Transport S ystem 95 SMF Family of Transporters 97 Siderophore-mediated Iron Uptake 97 Recovery of Iron from the Vacuole 98 4.4 Intracellular Iron Metabolism 99 4.4.1 Mitochondrial Iron Transport 100 4.4.2 Iron Storage in S. cerevisiae 101 4.5 Iron Transport in Other Fungi 101 4.6 References 102 5 Cellular Iron Uptake in Mammals 107 5.1 The Transferrins 107 5.1.1 Structure of Transferrins 108 5.1.2 Transferrin Iron Binding and Release 111 5.2 Iron Uptake by Mammalian Cells – Uptake of Transferrin-bound Iron 115 5.2.1 The Transferrin Receptor 115 5.2.2 Transferrin Binding to Its Receptor 118 5.2.3 Transferrin Receptor Binding to Hereditary Haemochromatosis Protein HFE 120 viii Contents 5.2.4 The Transferrin-to-cell Cycle 121 5.2.5 Receptor-independent Uptake of Transferrin Iron 124 5.3 Iron Uptake by Mammalian Cells – Uptake of Non-transferrin Bound Iron 124 5.3.1 Non-protein-Bound Iron 125 5.3.2 Ferritin-bound Iron 126 5.3.3 Haemopexin as an I ron Transporter 126 5.4 References 127 6 Intracellular Iron Storage and Biomineralization 133 6.1 Intracellular Iron Storage 133 6.1.1 Ferritin: Distribution and Primary Structure 134 6.1.2 Ferritin: Three-dimensional Structure 138 L-Chain Ferritins 139 H-chain Ferritins 145 Bacterioferritins 146 Ferritin-like Proteins 147 6.1.3 The Mineral Core 149 6.1.4 Iron Deposition in Ferritin 151 Iron Pathways into Ferritin 151 Iron Oxidation at Dinuclear Centres 152 Ferrihydrite Nucleation Sites 154 Crystal Growth 155 6.1.5 Iron Mobilization from Ferritin 156 6.1.6 Haemosiderin 157 6.2 Biomineralization 159 6.3 References 161 7 Intracellular Iron Metabolism and Cellular Iron Homeostasis 167 7.1 Intracellular Iron Metabolism 167 7.1.1 The Labile Iron Pool 167 7.1.2 Haem Biosynthesis 168 7.1.3 Friedrich’s Ataxia and Mitochondrial Iron Metabolism 171 Contents ix 7.1.4 Synthesis of Non-haem Iron Centres 172 7.1.5 Intracellular Haem Degradation – Haem Oxygenase 174 7.2 Metal Ion Homeostasis 176 7.2.1 Structural Features of IREs 178 7.2.2 Hereditary Hyperferritinaemia–Cataract Syndrome 180 7.2.3 mRNA T ranslation – IRE Translation Regulators 181 7.2.4 mRNA S tability – IRE Turnover Regulators 182 7.2.5 Iron Regulatory Proteins 1 and 2 183 7.3 References 186 8 Iron Absorption in Mammals with Particular Reference to Man 191 8.1 Iron Metabolism in Man: An Overview 191 8.2 Sources of Dietary Iron in Man and the Importance of Luminal Factors 192 8.3 Molecular Mechanisms of Mucosal Iron Absorption 194 8.3.1 Iron Uptake at the Apical Pole 196 8.3.2 Iron Transfer Across the Mucosal Cell 197 8.3.3 Release of Iron at the Basolateral Membrane and Uptake by Apotransferrin 199 8.4 A Model of Iron Uptake and Regulation of Iron Homeostasis by the Enterocyte 202 8.5 References 204 9 Pathophysiology of Iron Deficiency and Iron Overload in Man 207 9.1 Introduction: Acquired and Genetic Disorders of Iron Metabolism 207 9.2 Body Iron Regulation 208 9.2.1 Communication Between Iron Donor and Iron Acceptor Cells 208 9.2.2 Maintenance of Iron Balance in Cells 210 x Contents 9.3 Iron Absorption in Disorders of Iron Metabolism 211 9.3.1 Genotype and Phenotype of Animal and Human Iron Disorders 216 9.3.2 Macrophages and Hepatocytes in Disorders of Iron Metabolism 217 9.4 Iron Deficiency 220 9.4.1 Prevalence and Global Distribution of Iron Deficiency 220 9.4.2 Acquired Iron Deficiency 221 9.4.3 Genetic Forms of Iron Deficiency 221 9.4.4 Clinical Stages of Iron Deficiency 222 9.4.5 Symptoms and Signs of Iron Deficiency 223 9.4.6 Treatment of Iron Deficiency 223 9.5 Iron Overload 223 9.5.1 The b2m −/− Mouse as a Model for Human Hereditary Haemochromatosis 223 9.5.2 Adaptive Response of I ron Absorption in Iron-overload Diseases 224 9.5.3 Causes of Iron Overload 225 9.5.4 Heterogeneity of Phenotypes in Hereditary Haemochromatosis 225 9.5.5 Findings in C282Y Heterozygotes 227 9.5.6 Haemochromatosis and Porphyria Cutanea Tarda 227 9.5.7 Treatment of Iron Overload 228 9.6 Conclusion 228 9.7 References 229 10 Iron and Oxidative Stress 235 10.1 Introduction 235 10.2 Iron and Fenton Chemistry 235 10.2.1 Reactive Nitrogen Species 236 10.3 Importance of Cytoprotection 236 Glutathione (GSH) 237 10.3.1 Glutathione Reductase 238 10.3.2 Glutathione Peroxidase 238 10.3.3 Superoxide Dismutase 239 10.3.4 Catalase 239 10.3.5 Pentose Phosphate Pathway, PPP 239 10.3.6 Haem Oxygenase 240 10.4 Importance of Cell Type in Response to Oxidative Stress 240 10.4.1 Cancer Cells 241 10.4.2 Neutrophils and Macrophages 242 Contents xi 10.5 Natural Resistance-associated Macrophage Protein (Nramp1) 244 10.6 Ageing of Cells 244 10.7 Cell Signalling and Iron 244 10.7.1 Oxidative Stress in Bacteria 245 10.7.2 Oxidative Signalling in Yeast 245 10.7.3 Oxidative Stress in Plants 245 10.7.4 Oxidative Stress in Mammalian Cells 246 10.8 Apoptosis 249 10.9 Relationship Between NFKB and NO 249 10.10 How Does NO and H 2 O 2 Affect the Iron Regulatory Proteins IRP-1 and IRP-2 251 10.11 Diseases in which Increases in Iron may be Associated with Increased Oxidative Stress in the Cell 252 10.11.1 Iron and Inflammation 252 10.12 Diseases in which Iron Plays an Important Role 252 10.12.1 Genetic Haemochromatosis 252 10.12.2 Secondary Iron Overload 253 Thalassaemia 253 HIV 253 10.13 Neurodegenerative Diseases 253 Parkinson’s Disease 253 Alzheimer’s Disease 254 Friedrich’s Ataxia 255 10.14 References 255 11 Iron and Infection 259 11.1 Introduction 259 11.2 Microbial Strategies to Overcome the Iron-withholding Imposed by the Host, and its Potential Clinical Consequences 259 11.2.1 Siderophore Production 259 11.2.2 Binding of Diferric-transferrin or -lactoferrin 262 11.2.3 Binding of Haem-containing Compounds 264 [...]... understanding of iron metabolism since publication of the first edition of this book has been the application of the revolutionary techniques of molecular biology to identify new genes, their gene products involved in iron uptake and cellular utilization, and progressively to approach an understanding of their function The possible role of some of these new candidates implied in the uptake of iron across... foliage of the tree Come the springtime, all of these elements must be reassimilated from the soil by the roots and pumped, often many tens of metres, up to the branches where the leaves with their iron- intensive photosynthetic apparatus will be resynthesized In the case of iron, this will involve the uptake of soil iron by one or more of three basic strategies: (i) protonation, i.e acidification of the... 11.2.4 Reduction of Fe(III) and Uptake of Fe(II) 11.2.5 Multiple Intracellular Microbial Strategies 11.2.6 Comment 11.5 The Impact of Chronic Inflammation/Infection on Iron Metabolism 269 The Impact of Iron Excess on Infection 271 11.4.1 Iron Excess Increases the Risk and Aggravates the Outcome of Many Infections 11.4.2 What may be the Mechanisms? 11.3 11.4 266 266 269 271 273 The Role of Iron- related... Mars and Venus – Iron and Copper Introduction Copper Chemistry, Its Interactions with Iron, and Evolution Copper Chaperones Iron and Copper Interactions in Mammals and Man 12.2.2 Iron and Zinc Introduction Zinc Chemistry and Biochemistry Iron and Zinc Interactions in Man 12.2.3 Iron and Manganese Introduction Manganese Chemistry and Biochemistry Iron Manganese Interactions in Man 12.2.4 Iron and Cobalt... involved in iron metabolism for nearly forty years’ and make no apology for continuing to do so Over this time the importance of metals in biology – described as inorganic biochemistry or bioinorganic chemistry respectively by biochemists and inorganic chemists, and more recently neutralized by the appellation ‘biological inorganic chemistry – has been increasingly recognized The growth of interest in inorganic. .. stimulus in the preparation of a second edition, if only through seeing the well-thumbed copies of the first edition on your desks and bookshelves Another factor was hearing from so many of you about how useful you found the first edition for giving a panoramic view of iron metabolism from the point of view of a participant’ who was at least prepared to come down on one side of the fence, rather than the... oxidation of insoluble Cu(I) led to soluble Cu(II) As iron biochemistry evolved and changed, so too a new role of copper evolved with enzymes of higher redox potentials taking advantage of the oxidizing power of dioxygen In Roman mythology, allusions not only to interactions but even to connivances between Mars and Venus, leading even to seduction, abound (the superb representations of the love of Mars... the metabolism of iron and copper are intimately interconnected Though little remains from the Iron Age, compared with the to Bronze Age (the alloy of copper and tin), or gold and silver, iron always has the last word: ‘Gold is for the mistress – silver for the maid – Copper for the craftsman cunning at his trade.’ ‘Good !’ said the Baron, sitting in his hall, ‘But Iron – Cold Iron – is master of them... niches where the use of a metal other than iron for key metabolic roles was an evolutionary plus For the vast majority of living organisms, iron is absolutely necessary for the maintenance, the defence, the differentiation and last, but by no means least, the growth and cellular division of almost all living organisms That is why I have devoted this book to the inorganic biochemistry of iron References... diagram of a trimer from the EcBFR 24-mer (b) Ribbon diagram displaying one of the two types of trimeric interactions between monomers in the Dps dodecamer The acidic hole in the centre of the trimer connects the exterior of the dodecamer to the hollow core Note the similarity of this trimer to the EcBFR trimer in (a) (c) Ribbon diagram of the second type of trimeric interaction The hole in the centre of . Ltd ISBNs: 0-471-49223-X (Hardback); 0-470-84579-1 (Electronic) Inorganic Biochemistry of Iron Metabolism Inorganic Biochemistry of Iron Metabolism From Molecular Mechanisms to Clinical Consequences Second. Disorders of Iron Metabolism 207 9.2 Body Iron Regulation 208 9.2.1 Communication Between Iron Donor and Iron Acceptor Cells 208 9.2.2 Maintenance of Iron Balance in Cells 210 x Contents 9.3 Iron. in Disorders of Iron Metabolism 211 9.3.1 Genotype and Phenotype of Animal and Human Iron Disorders 216 9.3.2 Macrophages and Hepatocytes in Disorders of Iron Metabolism 217 9.4 Iron Deficiency