Iron Metabolism

Professor Robert Crichton, Department of Biochemistry, Université Catholique de Louvain, BelgiumProfessor 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.

'This textbook is clearly a milestone which should be to hand for every researcher and scholar working on or interested in the biochemistry and clinical aspects of iron. Those needing to go further in depth on some specific aspects will find not only an excellent starting point but also their pathway through the impressive list of references at the end of each chapter.' Acta Cryst (International Union of Crystallography), November 2017

• Preface xii1 Solution Chemistry of Iron 11.1 Iron Chemistry 11.2 Interactions of Iron with Dioxygen and Chemistry of Oxygen Free Radicals 21.3 Hydrolysis of Iron Salts 51.4 Formation and Characterisation of Ferrihydrite 71.5 Ageing of Amorphous Ferrihydrite to more Crystalline Products 101.6 Biomineralisation 111.7 Magnetite Biomineralisation by Magnetotactic Bacteria 131.7.1 Biogenesis of the Magnetosome Membrane 151.7.2 Protein Sorting 151.7.3 Chain Formation 161.7.4 Biomineralisation 161.7.5 A Model for Magnetosome Formation 17References 182 The Essential Role of Iron in Biology 222.1 Introduction: Iron an Essential Element in Biology 222.2 Physical Techniques for the Study of Iron in Biological Systems 252.3 Classes of Iron Proteins 292.4 Haemoproteins 292.4.1 Oxygen Carriers 302.4.2 Activators of Molecular Oxygen 342.4.3 Electron Transport Proteins 382.5 Iron–Sulphur Proteins 412.6 Non‐haem, Non‐Fe–S Proteins 482.6.1 Mononuclear Non‐haem Iron Enzymes 482.6.2 Dinuclear Non‐haem Iron Proteins 552.6.3 Proteins of Iron Storage, Transport and Metabolism 612.7 The Dark Side of Iron: ROS, RNS and NTBI 622.7.1 ROS and RNS 632.7.2 NTBI and LPI 64References 643 Microbial Iron Uptake 713.1 Introduction 713.2 Iron Uptake from Siderophores 743.2.1 Siderophores 743.2.2 Iron Transport across the Outer Membrane in Gram‐negative Bacteria 783.2.3 Transport across the Periplasm and Cytoplasmic Membrane in Gram‐negative Bacteria 863.2.4 Iron Uptake by Gram‐positive Bacteria 923.3 Fe2+ Transport Systems 933.4 Iron Release from Siderophores in the Cytoplasm 973.5 Intracellular Iron Metabolism 983.6 Control of Gene Expression by Iron 101References 1084 Iron Acquisition by Pathogens 1204.1 Introduction 1204.2 Host Defence Mechanisms, Nutritional Immunity 1214.3 Pathogenicity and PAIs 1234.4 Pathogen‐specific Iron Uptake Systems 1254.4.1 Siderophores Associated with Virulence 1254.4.2 Transferrin/lactoferrin Iron Uptake 1264.4.3 Haem Iron Uptake 1334.4.4 Ferrous Iron Uptake 1384.4.5 Ferric Citrate Uptake by Bacillus cereus 1414.5 Role of Fur and Fur Homologues in Virulence 1414.6 Role of Pathogen ECF Sigma Factors 1414.7 Fungal Pathogens 143References 1465 Iron Uptake by Plants and Fungi 1555.1 Iron Uptake by Plants 1555.1.1 Introduction 1555.1.2 Genome Sequencing 1575.1.3 Iron Acquisition by the Roots of Plants 1605.1.4 Long‐distance Iron Transport 1665.2 Iron Metabolism and Homeostasis in Plants 1695.2.1 New Tools in Plant Research 1695.2.2 Intracellular Iron Metabolism 1705.2.3 Plant Iron Homeostasis 1715.2.4 Diurnal Regulation of Iron Homeostasis 1765.3 Iron Uptake, Metabolism and Homeostasis in Fungi 1785.3.1 Introduction 1785.3.2 High‐ and Low‐affinity Iron Uptake Pathways 1795.3.3 Siderophore‐mediated Iron Uptake 1845.3.4 Intracellular Iron Metabolism 1855.3.5 Iron Homeostasis 186References 1906 Cellular Iron Uptake and Export in Mammals 2056.1 The Transferrins 2056.1.1 Introduction 2056.1.2 The Transferrin Family 2066.1.3 Structure of Transferrins 2116.1.4 Transferrin iron Binding 2156.1.5 Binding of other Metals by Transferrin 2186.2 Cellular Iron Uptake 2196.2.1 The Transferrin Receptors 2196.2.2 The Transferrin to Cell Cycle and Iron Release 2226.2.3 Iron Uptake from other Sources 2286.3 Cellular Iron Export 230References 2367 Mammalian Iron Metabolism and Dietary Iron Absorption 2477.1 An overview of Mammalian Iron Metabolism 2477.1.1 Introduction 2477.1.2 The Way Different Cells Handle Iron 2497.2 Mammalian Iron Absorption 2517.2.1 Introduction 2517.2.2 The Intestinal Mucosa 2527.2.3 Sources of Dietary Iron 2537.2.4 Iron Loss and Effects on Uptake 2557.3 Molecular Mechanisms of Mucosal Iron Absorption 2567.3.1 Iron Uptake at the Apical Pole 2567.3.2 Iron Transit through and Storage in Enterocytes 2597.3.3 Iron Efflux across the Basolateral Membrane 2597.3.4 Regulation of Iron Uptake by the Enterocyte 261References 2618 Intracellular Iron Utilisation 2658.1 Intracellular Iron Pools 2658.1.1 Introduction 2658.1.2 The Cytosolic Labile Iron Pool (LIP) 2668.1.3 Distribution of Iron in the Cytosol 2688.1.4 Other Intracellular Iron Pools 2698.2 Mitochondrial Iron Metabolism 2718.2.1 Mitochondrial Iron Uptake and Storage 2718.2.2 Mitochondrial Fe–S Protein Biogenesis 2718.2.3 Maturation of Cytosolic and Nuclear Fe–S Proteins 2758.2.4 Haem Biosynthesis 2838.3 Haem Oxygenase 2878.3.1 Structure and Catalytic Cycle 2878.3.2 Activation of Haem Oxygenase 1 (HO‐1) 292References 2929 Iron Storage Proteins 3009.1 Introduction 3009.2 The Ferritin Superfamily and Haemosiderins 3019.2.1 The Ferritin Superfamily 3019.2.2 Structure of Vertebrate and Invertebrate Ferritins 3049.2.3 Plant and Bacterial Ferritins 3089.2.4 Dps Proteins and Rubrerythrins 3139.2.5 The Mineral Core 3199.2.6 Haemosiderins 3199.3 Iron Uptake and Release from Ferritin 3209.3.1 Iron Uptake in Ferritins 3209.3.2 Iron Uptake in Dps Proteins 3339.3.3 Iron Release from Ferritin 3339.4 Biotechnological Applications of Ferritins 335References 33610 Cellular and Systemic Iron Homeostasis 34610.1 Cellular Iron Homeostasis 34610.1.1 Translational Control of Protein Synthesis 34610.1.2 The IRE/IRP System 34710.1.3 The IREs – distribution and Structure 34810.1.4 Structural Features of IRP1 and 2 35110.1.5 The IRE/IRP System Revisited – Iron Controls Iron 35310.1.6 Metabolic Consequences of Mutations in IREs 35710.2 Systemic Iron Homeostasis 35710.2.1 Introduction 35710.2.2 Hepcidin, the Key Player 35810.2.3 Factors which Regulate Hepcidin Synthesis 36010.3 Integration of Iron Homeostatic Systems 367References 36711 Iron Deficiency, Iron Overload and Therapy 37611.1 Iron‐deficiency Anaemia (IDA) 37611.1.1 Introduction – The Size of the Problem 37611.1.2 Causes of IDA 37811.1.3 Clinical Stages and Diagnosis of IDA 38011.1.4 Therapeutic Approaches 38311.1.5 Anaemia of Chronic Disease (ACD), Iron Refractory IDA (IRIDA) and Anaemia of Chronic Kidney Disease (CKD) 38411.2 Hereditary Iron Overload 38611.2.1 Introduction 38611.2.2 Hereditary Haemochromatosis (HH) 38611.2.3 Causes of HH 38711.2.4 Types of Haemochromatosis 38811.2.5 Therapy of Hereditary Haemochromatosis 39111.3 Acquired Iron Overload 39511.3.1 Introduction – Causes of Acquired Iron Overload 39511.3.2 Mechanisms of Iron Toxicity 39711.3.3 Evaluation of Iron Overload 39811.3.4 Chelation Therapy for Acquired Iron Overload 40011.3.5 Other Therapeutic Approaches 405References 40612 Iron and Immunity 41812.1 Introduction 41812.1.1 Innate Immunity 41912.2 The Key Role of Macrophages 42212.2.1 Overview 42212.2.2 Macrophage Phenotypes 42512.2.3 Microglia 42612.3 Effect of Iron Status on Phagocytic Cell Function 42912.3.1 Iron Deficiency 42912.3.2 Iron Overload 43012.4 Effect of Phagocytic Cell Function on Iron Metabolism 43112.4.1 The IRE–Iron Regulatory Protein (IRP) System 43112.5 Effector Molecules of the Innate Immune System 43312.5.1 Toll‐like Receptors 43312.5.2 NF‐κB 43312.5.3 Hypoxia‐Inducible Factor 1 (HIF 1) 43412.5.4 Haem Oxygenase 43512.5.5 DMT1, Nramp1 43712.6 Adaptive Immunity 43712.6.1 Cd8+ Lymphocytes and Cytotoxicity 43812.6.2 CD4+ lymphocytes 43812.7 Immune Function and other Factors 43812.7.1 Iron Supplementation and Immune Function 43812.7.2 Immune Function in the Elderly Population 43912.7.3 Iron Overload and Immune Function 43912.7.4 Thalassaemia 44012.8 Concluding Remarks 440References 44013 Iron and Oxidative Stress 44413.1 Oxidative stress 44413.1.1 Introduction – Milestones in the History of Life 44413.1.2 Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) 44713.1.3 Cellular Defence Mechanisms Against Oxidative Stress 45013.1.4 Role of ROS and RNS in Cell Signalling 46013.1.5 ROS, RNS and Oxidative Damage 466References 47614 Interactions between Iron and other Metals 48214.1 Introduction 48214.2 Iron Interactions with Essential Metals 48314.2.1 Copper 48314.2.2 Zinc 49414.2.3 Cobalt 49714.2.4 Manganese 50014.2.5 Calcium 50114.3 Iron Interactions with Toxic Metals 50214.3.1 Lead 50214.3.2 Cadmium 50314.3.3 Aluminium 505References 50715 Iron Homeostasis and Neurodegeneration 51615.1 Introduction 51615.2 Brain iron 51715.2.1 Brain Iron Homeostasis 51715.2.2 Aging and Brain Iron Content 51815.3 Iron and Neurodegeneration 52215.3.1 Introduction 52215.3.2 Adverse Effects of Iron in Neurodegeneration 52215.4 Neurodegeneration with Brain Iron Accumulation 52415.4.1 Aceruloplasminaemia 52415.4.2 Neuroferritinopathy 52615.4.3 Other NBIAs 52815.5 Other Monogenic Neurodegenerative Diseases 53015.5.1 Huntington’s Disease 53015.5.2 Friedreich’s Ataxia 53215.6 Neurodegeneration Involving Multiple Genes 53315.6.1 Parkinson’s Disease (PD) 53315.6.2 Alzheimer’s Disease (AD) 53515.6.3 Multiple Sclerosis (MS) 53715.7 Intracerebral Haemorrhage 538References 539Concluding Remarks 544Index 547