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Inorganic Biochemistry of Iron Metabolism From Molecular Mechanisms to Clinical Consequences, 2nd Edition - Robert R. Crichton

Contents


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

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

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

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

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

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

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

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

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

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