Inorganic biochemistry of iron metabolism

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 of 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 Across 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 Fe3+ 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 Fe3+ 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 System 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 Iron 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 Translation – IRE Translation Regulators 181 7.2.4 mRNA Stability – 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 Iron 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 H2O2 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 xii Contents 11.2.4 Reduction of Fe(III) and Uptake of Fe(II) 266 11.2.5 Multiple Intracellular Microbial Strategies 266 11.2.6 Comment 269 11.3 The Impact of Chronic Inflammation/Infection on Iron Metabolism 269 11.4 The Impact of Iron Excess on Infection 271 11.4.1 Iron Excess Increases the Risk and Aggravates the Outcome of Many Infections 271 11.4.2 What may be the Mechanisms? 273 11.5 The Role of Iron-related Genes on the Risk and Outcome of Infection 273 11.5.1 The Nramp1 Gene 274 11.5.2 The Haptoglobin Gene 276 11.6 Can Iron Depletion be Applied to Combat Infection? 277 11.6.1 Phlebotomy 277 11.6.2 Iron Chelators 277 11.6.3 Chloroquine 279 11.6.4 Vaccination 280 11.7 References 280 12 Interactions between Iron and other Metals 285 12.1 Introduction 285 12.2 Interactions Between Iron and Essential Metals 285 12.2.1 Mars and Venus – Iron and Copper 286 Introduction 286 Copper Chemistry, Its Interactions with Iron, and Evolution 287 Copper Chaperones 289 Iron and Copper Interactions in Mammals and Man 292 12.2.2 Iron and Zinc 294 Introduction 294 Zinc Chemistry and Biochemistry 295 Iron and Zinc Interactions in Man 296 12.2.3 Iron and Manganese 297 Introduction 297 Manganese Chemistry and Biochemistry 297 Iron–Manganese Interactions in Man 298 12.2.4 Iron and Cobalt 299 Cobalt Chemistry and Biochemistry 299 Iron–Cobalt Interactions in Man 301 Contents xiii 12.3 Iron and Toxic Metals 302 12.3.1 Iron and Aluminium 302 Introduction 302 Aluminium Chemistry and Biochemistry 303 Iron–Aluminium Interactions and Aluminium Toxicity 304 12.3.2 Iron and Lead 306 12.3.3 Cadmium 307 12.4 References 308 13 Concluding Remarks 313 13.1 References 318 Index