Mammalian Heme Peroxidases: Diverse Roles in Health and Disease (Oxidative Stress and Disease)

Mammalian heme peroxidase enzymes play a critical role in innate immune responses and disease prevention. The formation of potent chemical oxidants is essential to this protective physiologic activity in immunity. Although highly beneficial in the context of immune defense, it is now well established that peroxidases and their overproduction of oxidants contribute to the initiation and persistence of many chronic inflammatory conditions in the cardiovascular, neurologic, respiratory, renal, and gastrointestinal systems. Peroxidasins, a protein family related to heme peroxidases, play a novel role in tissue biogenesis and matrix assembly, which are also attracting attention in different pathological contexts. Given the diverse roles of mammalian heme peroxidases and the breadth and incidence of pathologies associated with these enzymes, there has been significant interest in modulating peroxidase activity as a therapeutic strategy. This book highlights recent developments in our understanding of the chemistry, biochemistry and biological roles of mammalian peroxidases and their associated oxidants, their involvement in both innate immunity and chronic inflammatory disease in a variety of end organs, and potential therapeutic approaches to modulate and prevent damaging reactions. Key Features Structure and biosynthesis of mammalian peroxidases Reactivity of hypohalous acids with biological substrates Peroxidases in innate immunity Peroxidases in human pathology Modulation of peroxidase-induced biological damage Cover Half Title Series Page Title Page Copyright Page Table of Contents Editors Contributors Part I • Introduction to Mammalian Heme Peroxidases 1 • EVOLUTION, STRUCTURE AND BIOCHEMISTRY OF HUMAN PEROXIDASES Abbreviations Heme Peroxidases Evolution and Functions of Peroxidases from the Peroxidase-Cyclooxygenase Superfamily Structure of the Peroxidase Domain of Human Peroxidases Biophysical Properties of Human Peroxidases Catalytic Properties of Human Peroxidases Conclusion Acknowledgements References 2 • BIOSYNTHESIS OF MAMMALIAN HEME PROTEINS, PEROXIDASES, AND NADPH OXIDASES Abbreviations Introduction Peroxidases Myeloperoxidase Biosynthesis of Related Peroxidases Eosinophil Peroxidase Lactoperoxidase Thyroid Peroxidase NOX Proteins NOX2 Other NOX Protein Family Members NOX1 NOX3 NOX4 NOX5 DUOX Conclusions Acknowledgments References 3 • PEROXIDASIN: STRUCTURE AND FUNCTION The Discovery of PXDN Structural Features of Human PXDN The Peroxidase Activity of PXDN Protein Interactions of PXDN Functional Aspects: Role of PXDN in the Organization of Basement Membranes PXDN Functions: Examples from Different Species Conclusion References Part II • Reactivity of Peroxidase Oxidants 4 • REACTIVITY OF PEROXIDASE-DERIVED OXIDANTS WITH PROTEINS, GLYCOPROTEINS AND PROTEOGLYCANS Abbreviations Introduction Sources and Outline of Biological Functions of Heme Peroxidases Catalytic Cycles of Heme Peroxidase Enzymes Substrate Specificities of Heme Peroxidases Targets of Hypohalous Acids Reactivity and Selectivity Products Formed on Modification of Amino Acid Side Chains Sulfur-Containing Side Chains: Cys, Met and Cystine Amines and Amides (Lys, N-Terminus, Gln, Asn) Guanidine (Amidine, Arg Side Chains) Imidazole Groups (His) Indole Groups (Trp) Aromatic Side Chains (Tyr) Products Formed from Sugar Residues Consequences of the Reaction of Hypohalous Acids with Proteins Cross-Linking and Aggregation Fragmentation Other Modifications to Protein Structure Conclusions Acknowledgments References 5 • REACTIVITY OF HYPOCHLOROUS ACID (HOCL) WITH NUCLEIC ACIDS, RNA AND DNA Abbreviations Introduction Formation of Chlorinated Products Reactive Intermediates – N-Chloramines and Nitrogen-Centered Radicals Stable Products – Chlorinated Nucleobases Structural Consequences of Nucleobase Chlorination Functional Consequences of Nucleobase Chlorination Mutagenesis Replication, Transcription and Translation Gene Silencing and Epigenetic Regulation Other Perturbations to Cellular Function Removal and Repair of Chlorinated RNA and DNA Damage The Role of Chlorinated Nucleosides in Health and Disease Therapeutic Use of Chlorinated Nucleosides Chlorinated Nucleosides as Biomarkers of Disease Concluding Remarks References 6 • REACTIVITY OF PEROXIDASE OXIDANTS WITH LIPIDS: THE GENERATION OF BIOLOGICALLY IMPORTANT MODIFIED LIPIDS Abbreviations Introduction Production of 2-Chlorofatty Aldehyde and Its Metabolites Detection and Quantification of 2-ClFALD and Metabolites Biological Effects and Signaling Pathways of 2-ClFALD and Its Metabolites Production of Chlorohydrins Detection and Quantification of Chlorohydrins Biological Effects and Signaling Pathways of Chlorohydrins Other MPO-Mediated Lipid Modifications Production of 2-Bromofatty Aldehyde and Bromohydrins Detection and Quantification of Brominated Lipids Biological Effects and Signaling Pathways of Brominated Lipids Production of Iodinated Lipids Detection and Quantification of Iodinated Lipids Biological Effects and Signaling Pathways of Iodinated Lipids Conclusion References 7 • ROLES OF MYELOPEROXIDASE IN THE OXIDATION OF APOLIPOPROTEINS: INTEREST OF MONITORING MYELOPEROXIDASE OXIDATION OF APOLIPOPROTEINS A-1 AND B-100 TO IMPROVE THE ESTIMATION OF LIPOPROTEIN QUALITY IN CARDIOVASCULAR DISEASES Abbreviations Evidence of Myeloperoxidase Impact in Cardiovascular Disease Pathophysiology of MPO in Atherosclerosis MPO and Dysfunctional-Proatherogenic Lipoproteins Activity of MPO on Lipoproteins Modifications of Apolipoprotein A-1 Modifications of Apolipoprotein B-100 Conclusion References 8 • GLOBAL PROFILING OF CELL RESPONSES TO (PSEUDO)HYPOHALOUS ACIDS (Pseudo)Hypohalous Acids (HOX): Chemistry, Biology, and Potential for Redox Signaling Non-Targeted Global Approaches to Elucidate Divergent Redox Signaling of HOX The Metabolome: Interface of HOX with Energy, Structure, and Function Applications of Metabolomics in Studies of HOX The Redox Proteome: A Major Player in HOX-Dependent Redox Signaling Applications of Redox Proteomics in Studies of HOX Integrating “-Omics” Data to Contextualize HOX Redox Biology Conclusions References Part III • Peroxidases in Innate Immunity 9 • MYELOPEROXIDASE AND IMMUNE CELL RECRUITMENT AND ACTIVATION Abbreviations Introduction MPO Activates Innate Immune Cells MPO-Dependent Effects Mediated by Receptor Binding MPO-Dependent Effects Mediated by Reactive Species Activation of Innate Immune Cells during MPO Deficiency or MPO Inhibition MPO Affects Innate Immune Cell Apoptosis MPO Induces Neutrophil NETosis MPO Affects Leukocyte Recruitment MPO-Dependent Leukocyte Recruitment via Modulation of the Vascular Endothelium MPO-Dependent Leukocyte Recruitment via Modulation of the Leukocyte MPO Affects Platelet Function MPO Regulates Adaptive Immunity Conclusion References 10 • BACTERICIDAL ACTIVITY OF THE OXIDANTS DERIVED FROM MAMMALIAN HEME PEROXIDASES Introduction Neutrophil Myeloperoxidase Secretory Fluid Lactoperoxidase Assessment of Bactericidal and Bacteriostatic Activity Bacterial Sensitivity to Hypochlorous Acid Bacterial Targets of Hypochlorous Acid and Chloramines Bacterial Sensitivity to Hypothiocyanous Acid Bacterial Targets of Hypothiocyanous Acid Future Directions Acknowledgments References 11 • PRIMING THE INNATE IMMUNE SYSTEM TO COMBAT RESPIRATORY DISEASE Abbreviations Innate Immunity Oxidant Generating Network in the Lung Antimicrobial Activity of the Lung’s Innate Immune Oxidants Inflammatory Cell Signaling by Innate Immune System Oxidants Harnessing Endogenous Innate Immunity Pathways to Diminish Inflammation in Respiratory Diseases Thiocyanate as an Antioxidant and Cloaked Oxidant Therapeutic Applications for the [sup(-)]SCN/HOSCN Redox Couple Antimicrobial Activities of the [sup(-)]SCN/HOSCN Redox Couple Anti-Inflammatory and Antimicrobiocidal Activities of [sup(-)]SCN/HOSCN Redox Couple in Cystic Fibrosis Lung Disease Conclusion References Part IV • Peroxidases in Pathology 12 • IMAGING THE REACTIVITY OF MYELOPEROXIDASE IN VIVO Introduction Agents That Detect MPO-Generated Reactive Species Fluorescence Imaging Bioluminescence Imaging (BLI) Miscellaneous Technologies Agents Based on MPO Substrates/Inhibitors Activatable Imaging Probes Targeting MPO 5-Hydroxyindol (5-HI)-Based Activatable Imaging Agents 5-HT-Based Imaging Agents MPO-Gd 5HT-DOTAGA-Gd Other 5-HI-Based Imaging Agents [sup(18)]F-MAPP: Positron Emission Tomography Imaging of MPO Activity MABS as a Platform for Fluorescence and CT Imaging of MPO Activity MABS with Streptavidin-Alexa-Fluoro647 (SAF-647) for Fluorescence Imaging MABS with Streptavidin-Gold Nanoparticles for CT Imaging Inhibitor-Based Imaging Probes Targeting Enzymatic MPO Perspectives References 13 • ROLE OF MYELOPEROXIDASE IN ENDOTHELIAL DYSFUNCTION AND ALTERED CELL SIGNALING IN ATHEROSCLEROSIS Vasoactive MPO Exerts Detrimental Effects on Endothelial Nitric Oxide Signaling Endothelial Intracellular Signaling Mechanisms Invoked by MPO-Derived Oxidants Endothelial Glutathione is a Major Target of MPO-Derived Oxidants MPO-Derived Oxidants Perturb Calcium Handling in Endothelial Cells Exposure to MPO-Derived Oxidants Causes Endothelial Cell Death Conclusion References 14 • MYELOPEROXIDASE IN ISCHEMIC HEART DISEASE Abbreviations Introduction MPO Promotes Endothelial Dysfunction Lipids and Lipoproteins and How They Are Affected by the Release of MPO Advanced Atherosclerotic Lesions – How MPO Affects Plaque Stability MPO Promotes Neointima Formation MPO in Myocardial Infarction Association of MPO and Cardiovascular Outcome Conclusion References 15 • THE ROLE OF MYELOPEROXIDASE IN NEURODEGENERATIVE DISEASE Introduction MPO Is a Double-Edged Sword MPO Expression in Brain Promotes Alzheimer’s Disease Amyloid Plaques Are a Defining Feature of AD MPO Generates Oxidants in AD MPO Is Abundant in AD Brain Co-localizing with Aβ in Amyloid Plaques MPO Is Expressed in Microglia Associated with Amyloid Plaques MPO Co-localizes with Aβ on the Walls of Blood Vessels in AD The -463G Promoter Polymorphism Is Associated with Increased Incidence of AD in Females ApoE4 Allele Correlates with Greater Deposition of MPO in Plaques in AD MPO-Generated Oxidants May Promote Aβ Aggregation Thereby Contributing to AD MPO Is Deposited in Plaques along with Aβ in a Transgenic Mouse Model Expressing the -463G MPO Allele MPO Co-localizes with Aβ in Plaques and on Vessel Walls in hMPO-APP23 as in AD Brain hMPO Is Expressed in Astrocytes in APP23 Mouse Brain MPO Is Expressed in GFAP-Positive Astrocytes in Human AD Brain MPO-APP23 Mice Exhibit Greater Memory Impairment Than APP23 Increased Lipid Peroxidation in MPOG-APP23 Brain The Role of Neutrophils in AD Conclusions from Studies of Human MPO Expression in AD and Mouse Models of AD The Role of MPO in Parkinson’s Disease MPO Is Expressed in PD Substantia Nigra Neurons But Not in Normal Aged Brain MPO Is Detected in Vesicles in PD SN Neurons That Also Contain αSyn Aggregates, Nitrated αSyn, and HOCl-Modified Epitopes MPO Expressed in hMPO-A53T Brain Is the Secreted 90 kDa Pro-MPO Form Human MPO Transgene Is Expressed in Neurons in the A53T Model of PD HOCl-Modified Epitopes in MPO-A53T Brain Carbamylation of αSyn by MPO in A53T Mouse Brain MPO Expression Exacerbates Motor Impairment in the hMPO-A53T Mice Conclusions from Studies of MPO in Parkinson’s Disease Why Is MPO Expressed in Astrocytes or Neurons in AD or PD Brain? The Role of MPO in Multiple Sclerosis The Role of MPO in the EAE Model of Multiple Sclerosis Conclusions Acknowledgments References 16 • THE PATHOGENESIS AND CONSEQUENCES OF MYELOPEROXIDASE-DEPENDENT ANCA VASCULITIS AND GLOMERULONEPHRITIS Abbreviations Introduction to MPO-ANCA Vasculitis ANCA Vasculitis Clinical and Pathologic Features Genetic Perturbations of MPO in ANCA Vasculitis MPO-ANCAs Are Pathogenic ANCAs Induce Myeloid Cell Activation and Degranulation to Injure Vessel Endothelium Altered Glycosylation of MPO-ANCA The Polyclonal MPO-ANCA Response Defines Disease Status T-Cell Responses Are MPO Epitope-Specific in Human and Murine Disease Targeting MPO in Antigen-Specific Immunotherapy Summary References 17 • ROLE OF PEROXIDASIN IN DISEASE Introduction Peroxidasin and Basement Membrane Homeostasis Peroxidasin Expression and Function in Mammals Peroxidasin in Eye Development Peroxidasin in Cardiovascular Disease Peroxidasin in Tissue Fibrosis Peroxidasin in Cancer Peroxidasin in Immunity Conclusion Acknowledgments References Part V • Prevention of Myeloperoxidase-Induced Damage 18 • STRUCTURE, FUNCTION, AND MECHANISTIC INSIGHTS INTO A NOVEL FAMILY OF MYELOPEROXIDASE INHIBITORY PROTEINS EXPRESSED BY STAPHYLOCOCCI Introduction SPIN: A Novel Myeloperoxidase Inhibitory Protein Expressed by Staphylococcus aureus Expression and Function of SPIN in Staphylococcal Evasion of Neutrophil Defense Defining the Structure/Function Relationships of the SPIN Protein Identification and Characterization of SPIN Homologs from Other Staphylococci Structure of SPIN from S. delphini Bound to Recombinant Human MPO Provides a Basis for Comparative Studies on SPIN-Class MPO Inhibitors Conclusion References Index "Peroxidasins are a family of heme peroxidases that play a novel role in tissue biogenesis and matrix assembly. Mammalian heme peroxidase enzymes are critical for immune responses and disease prevention. Although highly beneficial, overproduction drives the development of pathologies, including cardiovascular, neurodegenerative, respiratory, kidney and inflammatory bowel diseases by triggering the initiation of stress-related pathways leading to cell damage and dysfunction. This book highlights the roles of mammalian heme peroxidases, as well as their involvement in immunity and disease, and potential therapeutic approaches to modulate and prevent damaging reactions"-- Provided by publisher