Iron Metabolism
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portes grátis
Iron Metabolism
From Molecular Mechanisms to Clinical Consequences
Crichton, Robert
John Wiley & Sons Inc
05/2016
576
Dura
Inglês
9781118925614
15 a 20 dias
1350
Descrição não disponível.
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-?B 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
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-?B 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
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iron;metabolism;homeostasis;hepcidin;ferritin;transferrin;siderophore;chelator;deficiency;overload
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-?B 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
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-?B 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
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