Iron Metabolism

Professor Robert Crichton, Department of Biochemistry, Université Catholique de Louvain, Belgium Professor Crichton has worked on cytochrome c in Glasgow, insect haemoglobins in Munich, ferritins and transferrins in Glasgow and Berlin, and on all these areas plus new developments in the understanding of iron-protein interactions in Louvain-la-Neuve. He is the author of Metal-Based Neurodegeneration.

Preface xii

1 Solution Chemistry of Iron 1

1.1 Iron Chemistry 1

1.2 Interactions of Iron with Dioxygen and Chemistry of Oxygen Free Radicals 2

1.3 Hydrolysis of Iron Salts 5

1.4 Formation and Characterisation of Ferrihydrite 7

1.5 Ageing of Amorphous Ferrihydrite to more Crystalline Products 10

1.6 Biomineralisation 11

1.7 Magnetite Biomineralisation by Magnetotactic Bacteria 13

1.7.1 Biogenesis of the Magnetosome Membrane 15

1.7.2 Protein Sorting 15

1.7.3 Chain Formation 16

1.7.4 Biomineralisation 16

1.7.5 A Model for Magnetosome Formation 17

References 18

2 The Essential Role of Iron in Biology 22

2.1 Introduction: Iron an Essential Element in Biology 22

2.2 Physical Techniques for the Study of Iron in Biological Systems 25

2.3 Classes of Iron Proteins 29

2.4 Haemoproteins 29

2.4.1 Oxygen Carriers 30

2.4.2 Activators of Molecular Oxygen 34

2.4.3 Electron Transport Proteins 38

2.5 Iron–Sulphur Proteins 41

2.6 Non‐haem, Non‐Fe–S Proteins 48

2.6.1 Mononuclear Non‐haem Iron Enzymes 48

2.6.2 Dinuclear Non‐haem Iron Proteins 55

2.6.3 Proteins of Iron Storage, Transport and Metabolism 61

2.7 The Dark Side of Iron: ROS, RNS and NTBI 62

2.7.1 ROS and RNS 63

2.7.2 NTBI and LPI 64

References 64

3 Microbial Iron Uptake 71

3.1 Introduction 71

3.2 Iron Uptake from Siderophores 74

3.2.1 Siderophores 74

3.2.2 Iron Transport across the Outer Membrane in Gram‐negative Bacteria 78

3.2.3 Transport across the Periplasm and Cytoplasmic Membrane in Gram‐negative Bacteria 86

3.2.4 Iron Uptake by Gram‐positive Bacteria 92

3.3 Fe2+ Transport Systems 93

3.4 Iron Release from Siderophores in the Cytoplasm 97

3.5 Intracellular Iron Metabolism 98

3.6 Control of Gene Expression by Iron 101

References 108

4 Iron Acquisition by Pathogens 120

4.1 Introduction 120

4.2 Host Defence Mechanisms, Nutritional Immunity 121

4.3 Pathogenicity and PAIs 123

4.4 Pathogen‐specific Iron Uptake Systems 125

4.4.1 Siderophores Associated with Virulence 125

4.4.2 Transferrin/lactoferrin Iron Uptake 126

4.4.3 Haem Iron Uptake 133

4.4.4 Ferrous Iron Uptake 138

4.4.5 Ferric Citrate Uptake by Bacillus cereus 141

4.5 Role of Fur and Fur Homologues in Virulence 141

4.6 Role of Pathogen ECF Sigma Factors 141

4.7 Fungal Pathogens 143

References 146

5 Iron Uptake by Plants and Fungi 155

5.1 Iron Uptake by Plants 155

5.1.1 Introduction 155

5.1.2 Genome Sequencing 157

5.1.3 Iron Acquisition by the Roots of Plants 160

5.1.4 Long‐distance Iron Transport 166

5.2 Iron Metabolism and Homeostasis in Plants 169

5.2.1 New Tools in Plant Research 169

5.2.2 Intracellular Iron Metabolism 170

5.2.3 Plant Iron Homeostasis 171

5.2.4 Diurnal Regulation of Iron Homeostasis 176

5.3 Iron Uptake, Metabolism and Homeostasis in Fungi 178

5.3.1 Introduction 178

5.3.2 High‐ and Low‐affinity Iron Uptake Pathways 179

5.3.3 Siderophore‐mediated Iron Uptake 184

5.3.4 Intracellular Iron Metabolism 185

5.3.5 Iron Homeostasis 186

References 190

6 Cellular Iron Uptake and Export in Mammals 205

6.1 The Transferrins 205

6.1.1 Introduction 205

6.1.2 The Transferrin Family 206

6.1.3 Structure of Transferrins 211

6.1.4 Transferrin iron Binding 215

6.1.5 Binding of other Metals by Transferrin 218

6.2 Cellular Iron Uptake 219

6.2.1 The Transferrin Receptors 219

6.2.2 The Transferrin to Cell Cycle and Iron Release 222

6.2.3 Iron Uptake from other Sources 228

6.3 Cellular Iron Export 230

References 236

7 Mammalian Iron Metabolism and Dietary Iron Absorption 247

7.1 An overview of Mammalian Iron Metabolism 247

7.1.1 Introduction 247

7.1.2 The Way Different Cells Handle Iron 249

7.2 Mammalian Iron Absorption 251

7.2.1 Introduction 251

7.2.2 The Intestinal Mucosa 252

7.2.3 Sources of Dietary Iron 253

7.2.4 Iron Loss and Effects on Uptake 255

7.3 Molecular Mechanisms of Mucosal Iron Absorption 256

7.3.1 Iron Uptake at the Apical Pole 256

7.3.2 Iron Transit through and Storage in Enterocytes 259

7.3.3 Iron Efflux across the Basolateral Membrane 259

7.3.4 Regulation of Iron Uptake by the Enterocyte 261

References 261

8 Intracellular Iron Utilisation 265

8.1 Intracellular Iron Pools 265

8.1.1 Introduction 265

8.1.2 The Cytosolic Labile Iron Pool (LIP) 266

8.1.3 Distribution of Iron in the Cytosol 268

8.1.4 Other Intracellular Iron Pools 269

8.2 Mitochondrial Iron Metabolism 271

8.2.1 Mitochondrial Iron Uptake and Storage 271

8.2.2 Mitochondrial Fe–S Protein Biogenesis 271

8.2.3 Maturation of Cytosolic and Nuclear Fe–S Proteins 275

8.2.4 Haem Biosynthesis 283

8.3 Haem Oxygenase 287

8.3.1 Structure and Catalytic Cycle 287

8.3.2 Activation of Haem Oxygenase 1 (HO‐1) 292

References 292

9 Iron Storage Proteins 300

9.1 Introduction 300

9.2 The Ferritin Superfamily and Haemosiderins 301

9.2.1 The Ferritin Superfamily 301

9.2.2 Structure of Vertebrate and Invertebrate Ferritins 304

9.2.3 Plant and Bacterial Ferritins 308

9.2.4 Dps Proteins and Rubrerythrins 313

9.2.5 The Mineral Core 319

9.2.6 Haemosiderins 319

9.3 Iron Uptake and Release from Ferritin 320

9.3.1 Iron Uptake in Ferritins 320

9.3.2 Iron Uptake in Dps Proteins 333

9.3.3 Iron Release from Ferritin 333

9.4 Biotechnological Applications of Ferritins 335

References 336

10 Cellular and Systemic Iron Homeostasis 346

10.1 Cellular Iron Homeostasis 346

10.1.1 Translational Control of Protein Synthesis 346

10.1.2 The IRE/IRP System 347

10.1.3 The IREs – distribution and Structure 348

10.1.4 Structural Features of IRP1 and 2 351

10.1.5 The IRE/IRP System Revisited – Iron Controls Iron 353

10.1.6 Metabolic Consequences of Mutations in IREs 357

10.2 Systemic Iron Homeostasis 357

10.2.1 Introduction 357

10.2.2 Hepcidin, the Key Player 358

10.2.3 Factors which Regulate Hepcidin Synthesis 360

10.3 Integration of Iron Homeostatic Systems 367

References 367

11 Iron Deficiency, Iron Overload and Therapy 376

11.1 Iron‐deficiency Anaemia (IDA) 376

11.1.1 Introduction – The Size of the Problem 376

11.1.2 Causes of IDA 378

11.1.3 Clinical Stages and Diagnosis of IDA 380

11.1.4 Therapeutic Approaches 383

11.1.5 Anaemia of Chronic Disease (ACD), Iron Refractory IDA (IRIDA) and Anaemia of Chronic Kidney Disease (CKD) 384

11.2 Hereditary Iron Overload 386

11.2.1 Introduction 386

11.2.2 Hereditary Haemochromatosis (HH) 386

11.2.3 Causes of HH 387

11.2.4 Types of Haemochromatosis 388

11.2.5 Therapy of Hereditary Haemochromatosis 391

11.3 Acquired Iron Overload 395

11.3.1 Introduction – Causes of Acquired Iron Overload 395

11.3.2 Mechanisms of Iron Toxicity 397

11.3.3 Evaluation of Iron Overload 398

11.3.4 Chelation Therapy for Acquired Iron Overload 400

11.3.5 Other Therapeutic Approaches 405

References 406

12 Iron and Immunity 418

12.1 Introduction 418

12.1.1 Innate Immunity 419

12.2 The Key Role of Macrophages 422

12.2.1 Overview 422

12.2.2 Macrophage Phenotypes 425

12.2.3 Microglia 426

12.3 Effect of Iron Status on Phagocytic Cell Function 429

12.3.1 Iron Deficiency 429

12.3.2 Iron Overload 430

12.4 Effect of Phagocytic Cell Function on Iron Metabolism 431

12.4.1 The IRE–Iron Regulatory Protein (IRP) System 431

12.5 Effector Molecules of the Innate Immune System 433

12.5.1 Toll‐like Receptors 433

12.5.2 NF‐κB 433

12.5.3 Hypoxia‐Inducible Factor 1 (HIF 1) 434

12.5.4 Haem Oxygenase 435

12.5.5 DMT1, Nramp1 437

12.6 Adaptive Immunity 437

12.6.1 Cd8+ Lymphocytes and Cytotoxicity 438

12.6.2 CD4+ lymphocytes 438

12.7 Immune Function and other Factors 438

12.7.1 Iron Supplementation and Immune Function 438

12.7.2 Immune Function in the Elderly Population 439

12.7.3 Iron Overload and Immune Function 439

12.7.4 Thalassaemia 440

12.8 Concluding Remarks 440

References 440

13 Iron and Oxidative Stress 444

13.1 Oxidative stress 444

13.1.1 Introduction – Milestones in the History of Life 444

13.1.2 Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) 447

13.1.3 Cellular Defence Mechanisms Against Oxidative Stress 450

13.1.4 Role of ROS and RNS in Cell Signalling 460

13.1.5 ROS, RNS and Oxidative Damage 466

References 476

14 Interactions between Iron and other Metals 482

14.1 Introduction 482

14.2 Iron Interactions with Essential Metals 483

14.2.1 Copper 483

14.2.2 Zinc 494

14.2.3 Cobalt 497

14.2.4 Manganese 500

14.2.5 Calcium 501

14.3 Iron Interactions with Toxic Metals 502

14.3.1 Lead 502

14.3.2 Cadmium 503

14.3.3 Aluminium 505

References 507

15 Iron Homeostasis and Neurodegeneration 516

15.1 Introduction 516

15.2 Brain iron 517

15.2.1 Brain Iron Homeostasis 517

15.2.2 Aging and Brain Iron Content 518

15.3 Iron and Neurodegeneration 522

15.3.1 Introduction 522

15.3.2 Adverse Effects of Iron in Neurodegeneration 522

15.4 Neurodegeneration with Brain Iron Accumulation 524

15.4.1 Aceruloplasminaemia 524

15.4.2 Neuroferritinopathy 526

15.4.3 Other NBIAs 528

15.5 Other Monogenic Neurodegenerative Diseases 530

15.5.1 Huntington’s Disease 530

15.5.2 Friedreich’s Ataxia 532

15.6 Neurodegeneration Involving Multiple Genes 533

15.6.1 Parkinson’s Disease (PD) 533

15.6.2 Alzheimer’s Disease (AD) 535

15.6.3 Multiple Sclerosis (MS) 537

15.7 Intracerebral Haemorrhage 538

References 539

Concluding Remarks 544

Index 547