This book provides a unique, comprehensive, and up-to-date overview of the various NADPH oxidases and narrates the history of their discovery, biochemical characteristics, genetics, molecular structure, and multiple functions in health and disease. It covers the subject in a manner that serves both the expert and the novice researcher in the field.
The book starts with an overview of the major milestones in the discovery of the archetypical NADPH oxidase, known as cytochrome b558, and its cytosolic regulators. This is followed by personal recollections by pioneers of the field, descriptions of the work of the major figures of the past by their followers, and a rendering of the history of the discovery of the Nox family. The central section of the book consists of chapters devoted specifically to an in depth description of the individual members of the Nox family, and is followed by chapters focused on the modulators of their function. A subsequent section comprises chapters dealing with methodologies of Nox research, interaction with other proteins, and Nox inhibitors. A distinct section of the book deals with non-mammalian Noxs, from amoeba to zebrafish. Subsequent chapters focus on Nox structure, a field in which extraordinary progress was made in recent years. The volume ends with chapters on Chronic Granulomatous Disease, the consequence of Nox loss-of-function, and its treatment by gene therapy. The coda is a crystal ball perspective of the hopes for the clinical translation of basic Nox research.
Written for biochemists, cell biologists, molecular biologists, and clinicians, this book is aimed at both senior scientists and young investigators in the field.
Author(s): Edgar Pick (editor)
Publisher: Springer
Year: 2023
Language: English
Pages: 582
City: Cham
Preface
Contents
Part I: History, Recollections, and Homages
1: Paradigm Shifts in the History of Nox2 and Its Regulators: An Appreciative Critique
1 Prehistory
1.1 The ``Respiration´´ of Phagocytes: The First Paradigm
1.2 A Dominant Biochemist Enters the Field: Manfred L. Karnovsky and a Fluctuating Paradigm
1.3 Karnovsky´s Alter Ego: Judah Hirsch Quastel
2 History
2.1 A Gentleman from Verona: Filippo Rossi
2.2 A Minor Diversion
2.3 Two Stars are Born: The Person and the Radical
2.4 The New ``Yellow Enzyme´´
2.5 The Flavoprotein Becomes the Prima Donna: The Era of the Binary NADPH Oxidase
2.6 Off the Path, Briefly
2.7 The Campaign to Purify the Pre-activated NADPH Oxidase
2.8 The Cytochrome Deniers
2.9 Before ``Curtain Down´´
3 ``Modern Times´´: The Transition to Molecular NADPH Oxidase Research
3.1 Cytochrome b558 Phylogeny: The Pink Oxidase
3.2 The Cytochrome b Revolution
3.3 Challenging the Cytochrome Revolution
3.4 ``The Gold Rush´´: The Race to Purify the Cytochrome
3.5 Cytochrome at Work: O2- Production by Purified Cytochrome b558
3.6 No ``Rapping´´ in Cytochrome b558
3.7 Filling in the Blanks: Heme Coordination: Six or Five?
3.8 Platonic Love: Cytochrome b558 Heme Iron and Oxygen Keep Distance
4 Cytochrome b558: A Roundup
4.1 ``Clone or Perish´´: Reverse Genetics in Action
4.2 ``Forget-Me-Not´´: The p22phox Gene
4.3 Hide-and-Seek: Where Are the Hemes?
4.4 Bis-Heme Motif Archeology: Ferric Reductases
5 From the Golden Calf to NADPH Oxidase Monotheism
5.1 Functional Evidence for the Presence of All Redox Stations on Cytochrome b558
5.2 Identifying the Binding Site for NADPH: A Bumpy Road
5.3 ``The Wrong Man´´
5.4 Briefly, Back to FAD
5.5 In Silico Apotheosis: Copy-Pasting from Ferredoxin-NADP+ Reductase
5.6 The Enigmatic Insertion Sequence
5.7 A Retrograde Paradigm Shift Attempt: ``Nobody´s Perfect´´
6 The Unexpected Emergence of the Cytosol
6.1 A Disputed Birth Certificate
6.2 The Cell-Free System
6.3 Meanwhile, in Ghent
6.4 A Controversial Background Nevertheless Leads to Doing the Right Experiments
6.5 The Cell-Free Becomes ``Legit´´
6.6 Cell-Free Activators: Beyond Fatty Acids
6.7 An Unnoticed Paradigm Shift: Assembly and Catalysis
6.8 The Poor Man´s Cell-Free: Renouncing the Cytosol
7 The Cytosolic Aristocracy: p47phox and p67phox
7.1 The Unlikely Road to Success: The Wrong Affinity Gels Yield the Right Proteins and a Notorious Rabbit Emerges
7.2 Cloning of p47phox and p67phox Following Isolation: ``The Last of the Mohicans´´ Approach
8 Evolution Runs Out of Genes and Has to Borrow from Neighbors
8.1 The Exhilaration of Identifying a ``New Protein´´ and the Frustration of Finding That It Was Already Known
8.1.1 Getting Help from GEFs
8.1.2 Untypical Rac CGDs
8.2 Divorce, Rac-RhoGDI Style
8.2.1 A Paradigm Shift: GEF Is Responsible for the Divorce
8.2.2 An Unresolved Dissonance
9 A Protein For all Seasons: p67phox Emerges as the Direct Nox2 Activator
9.1 Binding of Cytosolic Components to Nox2: More Questions than Answers
9.2 p67phox and p47phox: The Indispensable Activator and the Dispensable Organizer
9.3 The Unexpected Regulator of p67phox
9.3.1 Your Old Road Is Rapidly Agin ` For the Times They Are A-Changin´
10 An Induced Conformational Change in Nox2 Affects the Electron Flow: How and Where?
10.1 The Expected Paradigm Shift: A Conformational Change in Nox2 Affects Distances Between Redox Stations
10.2 Is the C-terminal F570 Involved in Nox2 Activation?
11 A Major Paradigm Shift: Relief of Autoinhibition as the Mechanism of Activation of Nox2 Organizer and Activator
11.1 Awakening the Dormant p47phox
11.2 p47phox Acquires a Taste for Lipids by Abandoning an Autoinhibitory ``Diet´´
11.3 Targeting Nox2 Activation by p22phox Peptides
11.4 Mimicking PKC Action In Vitro: An Alternative to Amphiphile-Dependent Cell-Free NADPH Oxidase Activation
11.5 Physico-Chemical Evidence for an Induced Conformational Change in p47phox
11.6 Alternative Pathways of In Vitro Nox2 Activation
11.6.1 Truncation of Cytosolic Components
11.6.2 Prenylation-Dependent Amphiphile-Independent Nox2 Activation
11.6.3 Replacing the Anionic Amphiphile with Anionic Membrane Phospholipids
11.6.4 GEF-Assisted Nox2 Activation
11.7 Autoinhibition in p67phox - ``Et Tu Brute?´´
11.8 A Serendipitous Finding Reveals a Hidden Target in Nox2
12 ``Curtain Up´´ Again
12.1 Back to the Future
12.2 The Missing Finale
13 Epilogue
References
2: The Phagocyte Oxidase: The Early Years
1 Prologue
2 Introduction
3 Early Days
4 Superoxide
5 NADH Oxidase vs. NADPH Oxidase
6 Coda and Dedication
Appendix: The Phagocyte in ImmunologyHistory
References
3: Reflections on My Life in Noxes
1 Overview and Dedication
2 Roots and the Importance of Mentors
3 The Prehistoric Era of the Phagocyte NADPH Oxidase
4 The ``Only Child´´ Comes of Age: Identification of the Components of the Phagocyte Oxidase
5 Sorting Out the Protein-Protein Interactions That Regulate the Phagocyte NADPH Oxidase
6 Discovery of the Activation Domain of p67phox and Its Regulation of Hydride Transfer from NADPH to FAD
7 Discovery of the Noxes and Duoxes: The Only Child Becomes a Member of a Family
8 What in the World Are All These Nox and Duox Enzymes Doing?
9 Nox4, the Odd-Ball of the Family: An Oxygen-Sensing Enzyme?
10 Similarities and Differences Among Nox/Duox Enzymes
11 Nox Enzymes and Human Diseases
12 Adventures (Misadventures?) in Drug Discovery
References
4: The Discovery and Characterisation of Nox2, a Personal Journey
1 Introduction
2 Discovery of the Nature of the NADPH Oxidase
3 NOX2 and Chronic Granulomatous Disease
4 Characterisation and Purification of the Cytochrome b
5 The Search for Other Electron Transport Carriers
5.1 Flavin and NADPH Binding Components
5.2 FAD
5.3 Other Electron Transporting Molecules
5.4 The Location of the NADPH Binding Site
6 Purification and Characterisation of the Flavocytochrome b
7 Identification of the Second Flavocytochrome (23 kDa) Subunit
8 Further Studies into the Structure of gp91phox
8.1 Building a Model
8.2 Location of the Haems
9 The Discovery of Accessory Activating Molecules
9.1 p47 phox and p67 phox
9.2 p21Rac and GDI
9.3 p40 phox
10 The Function of NOX2 and the Probable Function of Other NOXs
10.1 Oxygen Free Radicals and the Role of Myeloperoxidase
10.2 The Influence of NOX2 on Conditions Within the Phagocytic Vacuole
10.3 The K+ Channel
11 NOXs as Electrochemical Generators of Ion Fluxes
11.1 NOX3 and the Head-Tilt Mouse
11.2 NOXs in the Generation of Osmotic Pressure (Considered in Greater Depth in Reference [82])
12 Conclusion
References
5: Reminiscences on Positional Cloning of X-CGD Gene (Aka CYBB, gp91phox, Nox2)
1 Background
2 Searching for the X-CGD Gene
3 The Proof: A Eureka Moment
4 Subsequent Studies from Our Group and Collaborators
5 Reflections on Our Success
6 Some Thoughts on Impact of Science on Patients
References
6: On Katsuko Kakinuma: Spectroscopic Studies of Redox Centers in NADPH Oxidase -``Identifying and Observing the Key Players t...
1 Introduction
2 The Source of the Electron Used in the Neutrophil Oxidase System: NADPH or NADH?
2.1 Chemicals Similar to Substances That Are Phagocytosed
2.2 NADPH vs NADH Oxidation, to Couple with Superoxide Generation by Neutrophils [4-6]
3 Flavin, a Key Player Capable of Promoting Oxidation-Reduction Reactions
4 Heme: Another Key Player in the Transfer of an Electron to Oxygen
5 Epilogue
References
7: Pierre Vignais, from One Respiratory Chain to Another
References
8: Gary M. Bokoch, the Rac-n-Rho Man: His Fascination with Rho-GTPases
1 Introduction
2 Gary´s Early Career
3 The Hunt for Low Molecular Weight G-Proteins in Neutrophils and HL-60 Cells
4 The Balancing of Projects
5 My Story
6 The Difficult Project
7 New Beginnings: NOX1
8 The Continuation of Gary´s Lab by Dr. Céline DerMardirossian
9 Anecdotes About Gary
10 Conclusion
References
9: History and Discovery of the Noxes: From Nox1 to the DUOXes
1 Introduction
2 Oxidative Biochemistry in Sea Urchin Reproduction
3 Thyrocytes Produce H2O2 for Biosynthesis of Thyroid Hormone
4 From ``Oxidative Stress´´ to ``Redox Signaling´´: First Discovery of NADPH Oxidase Homologs
5 The NOX Family Expands: From Plants to Fungi and Bacteria
6 General Aspects of NOX Biology
7 Final Outlook
References
Part II: Canonical NADPH Oxidases
10: NADPH Oxidase 1: At the Interface of the Intestinal Epithelium and Gut Microbiota
1 Introduction
2 NOX1, the Close Cousin of the NOX2-Based Oxidase of Phagocytes
2.1 Structural Features of the NOX1-Based Flavocytochrome
2.2 NOX1: A Regulated Multicomponent Oxidase Complex
2.3 Other NOX1 Regulators
3 NOX1 Functions in Innate Immunity
4 NOX/DUOX Deficiencies in Inflammatory Bowel Disease (IBD)
4.1 Human NOX1 Deficiencies in IBD
4.2 Human NOX2 Deficiencies in IBD
4.3 Human DUOX2 Deficiencies in IBD
4.4 Mouse Models of IBD Related to NOX1, NOX2 and DUOX2 Deficiency
5 NOX1 in Other Systemic Inflammatory Diseases
6 NOX1 in Cancer Revisited
7 Summary and Conclusions
References
11: Physiological Functions and Pathological Significance of NADPH Oxidase 3
1 Introduction
2 Expression and Subunit Composition of a NOX3-Containing Enzyme Complex in the Inner Ear
2.1 Pattern of Nox3 Expression Across Organs
2.2 Subunit Composition of the NOX3-Containing Enzyme Complex
3 Physiological Functions of NOX3
3.1 Physiological Function of NOX3 in the Inner Ear
3.2 Proposed Roles of NOX3 in the Genesis of Otoconia
3.3 Physiological Functions of NOX3 Outside of the Inner Ear
4 Pathological Significance of NOX3
4.1 Pathological Effects of NOX3 in the Inner Ear
4.2 Pathological Effects of NOX3 Outside of the Inner Ear
5 Conclusions
References
12: Nox4: From Discovery to Pathophysiology
1 Introduction
2 Structure and Expression
2.1 Tissue Distribution
2.2 Subcellular Distribution
2.3 H2O2 Production by Nox4
3 Regulation of Expression and Activity
4 Physiological Functions
4.1 Growth/Differentiation
4.2 Senescence
4.3 Apoptosis/Survival
4.4 Cytoskeletal Rearrangement
4.5 Oxygen Sensing
4.6 ER Stress and Autophagy
4.7 Mitochondrial Function and Metabolism
5 Role in (Patho)physiology
5.1 Myocardial Development and Hypertrophy
5.2 Myocardial Ischemia
5.3 Vascular Disease
5.4 Hypertension
5.5 Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS)
5.6 Pulmonary Hypertension (PH)
5.7 Chronic Obstructive Pulmonary Disease (COPD)
5.8 Fibrotic Disease
5.8.1 Lung Fibrosis
5.8.2 Hepatic Fibrosis
5.9 Kidney Disease
5.10 Diabetes/Insulin signaling
5.11 Bone Remodeling
5.12 Angiogenesis
5.13 Cancer
5.14 Neurodegenerative Disorders
5.15 Stroke
6 Inhibitors
6.1 APX-115
6.2 GLX
6.3 Setanaxib
7 Conclusion
References
13: Nox5: Molecular Regulation and Pathophysiology
1 Introduction
2 Evolution and Discovery of Eukaryotic Nox5
3 Structure of Nox5
4 Regulation of Nox5
4.1 Calcium-Dependent Activation of Nox5
4.2 Regulatory Proteins
4.3 Molecular Chaperones
4.4 Regulation of Nox5 by Nitric Oxide
4.5 Post-Translational Modifications
4.5.1 Nox5 Phosphorylation
4.5.2 Nox5 Oxidation
4.5.3 Nox5 S-Nitrosylation
4.5.4 SUMOylation of Nox5
4.6 Genetic Regulation
5 Nox5 as a Proton Pump and Effect on Intracellular pH
6 Cellular and Tissue Distribution of Nox5
7 Subcellular Localization of Nox5
8 Nox5 and Signaling
9 Physiological Role of Nox5
9.1 Nox5 and Sperm Function
9.2 Nox5 and Contraction
10 Nox5 and Disease
10.1 Hypertension
10.2 Atherosclerosis
10.3 Aortic Aneurysm and Vascular Calcification
10.4 Small Vessel Disease of the Brain
10.5 Heart Disease
10.6 Kidney Disease
10.7 Hirschsprung Disease and Nox5
10.8 Nox5 and Cancer
11 Conclusions
References
14: DUOX1 and DUOX2, DUOXA1 and DUOXA2
1 The Story of DUOX and the Thyroid: H2O2 Is Needed for Thyroid Hormone Synthesis
2 DUOX1 and DUOX2: Cloning from the Thyroid
3 DUOX-DUOXA Is the Active Enzyme Complex
4 DUOX-DUOXA Defects in Congenital Hypothyroidism
5 DUOX-DUOXA and Thyroid Carcinogenesis
6 DUOX in Association with Peroxidases Is Involved in Tyrosine Cross-Linking
7 DUOX and Host Defense
7.1 DUOX Immune Function in the Respiratory Epithelium
7.2 DUOX Immune Function in the Gastrointestinal Tract
8 Conclusion (Table 14.1)
References
Part III: NADPH Oxidase Regulators
15: p47phox and NOXO1, the Organizer Subunits of the NADPH Oxidase 2 (Nox2) and NADPH Oxidase 1 (Nox1)
1 Overview
2 p47phox, the Phagocyte NADPH Oxidase Organizer and Regulator
2.1 History of the Discovery of p47phox
2.2 Structure of p47phox
2.3 Phosphorylation of p47phox
2.3.1 Phosphorylation of p47phox Is Required for NADPH Oxidase/NOX2 Activation
2.3.2 Phosphorylation of p47phox Regulates NADPH Oxidase/NOX2 Priming
2.3.3 Phosphorylation of p47phox Is Regulated by p67phox and p40phox
2.3.4 Phosphorylation of p47phox Induces p47phox Conformational Changes and its Interaction with p22phox
3 NOXO1, the NOX1 Organizer and Regulator
3.1 History of NOXO1 Discovery
3.2 Structure of NOXO1
3.3 Phosphorylation of NOXO1
3.4 NOXO1 Expression
4 Conclusions
References
16: The NADPH Oxidase Activator p67phox and Its Related Proteins
1 Introduction
2 p67phox (NoxA2)
3 NoxA1, a Vertebrate p67phox-Homologous Oxidase Activator
4 NoxR, a Fungal p67phox-Related Protein that Regulates NoxA and NoxB
5 Epilogue
References
17: p40phox: Composition, Function and Consequences of Its Absence
1 Introduction
2 Role in NADPH Oxidase Activation
3 Role in NADPH Oxidase Localization
4 Role in NADPH Oxidase Activity Regulation
5 Role in Inflammatory Reactions
6 Differences Between Mice and Men
7 Clinical Phenotype in Patients
References
18: Rho Family GTPases and their Modulators
1 Introduction
2 Family of Rho GTPases: An Overview
3 Regulation of Rho GTPases
3.1 Guanine Nucleotide Exchange Factors (GEFs)
3.2 GTPase Activating Proteins (GAPs)
3.3 Guanine-Nucleotide Dissociation Inhibitors (GDIs)
3.4 Lipid Modification and the Polybasic Region Dictate Rho GTPase Subcellular Localization
3.5 Other Posttranslational Modifications
4 Effectors of Rho GTPases
4.1 Major Effectors for Rho, Rac, and Cdc42 Subfamilies
4.2 Effector Activation Mechanisms
4.3 Rac GTPases in the Activation of NADPH Oxidases
5 Structural Aspects of Rho GTPase Regulation
5.1 The Molecular Switch Mechanism
5.2 Dynamics of the Switch Regions and Conformational Equilibrium
5.3 Structural Diversity of Rho Regulators and Effectors
5.4 Dynamics and Allostery Contributing to Substrate Specificity
6 Rho GTPase Function in Physiological Processes and Human Diseases
6.1 Genetic Analysis of Rac Subfamily GTPases
6.2 Rho GTPases in Human Diseases
6.3 Therapeutic Targeting
7 Conclusion and Perspectives
References
Part IV: Tools, Inhibitors, and Neighbors
19: Tools to Identify Noxes and their Regulators
1 Introduction
1.1 History and First Discoveries
1.2 Finding the Homologues
1.3 How to Identify the Interactors and their Function?
1.4 Targeted Approaches
1.4.1 Rac
1.4.2 p22phox
1.4.3 Nox4
1.4.4 Nox5 in Ca2+ Dependent ROS Formation
1.5 Untargeted Approaches and Outlook
1.5.1 Untargeted Analysis of Protein-Protein Interaction
1.5.2 Non-protein Regulators
1.5.3 Artificial Intelligence
References
20: Methods to Measure Reactive Oxygen Species Production by NADPH Oxidases
1 Introduction
2 Detection of Nox-Derived Superoxide
2.1 Chemical Properties of Superoxide
2.2 Small Molecule Probes for Superoxide
2.2.1 Reduction of Ferricytochrome c
2.2.2 Reduction of Tetrazolium Salts
2.2.3 Lucigenin Chemiluminescence
2.2.4 Oxidation of Luminol and Analogs
2.2.5 Oxidation of Coelenterazine and Analogs
2.2.6 Oxidation of Ethidium-Based Probes
2.2.7 EPR Spin Trapping
2.2.8 Other Probes for O2-
3 Detection of Hydrogen Peroxide
3.1 Chemical Properties of H2O2
3.2 Small Molecule Probes for H2O2
3.2.1 Oxidation of Reduced Fluorophores
3.2.2 Oxidation of Luminol and Analogs
3.2.3 Oxidation of Amplex Red
3.2.4 Oxidation of Other Phenolic Probes
3.2.5 Oxidation of Boronates
3.2.6 Other Probes for H2O2
4 Simultaneous Detection of O2- And H2O2
5 Recommendations and Outlook
References
21: Isoform-Selective Nox Inhibitors: Advances and Future Perspectives
1 Introduction
2 The NADPH Oxidases: A Brief Overview as a Prelude to Therapeutic Modalities
3 Challenges of Druggable NOX inhibition
4 NOX Targeting Strategies: Advantages and Drawbacks
5 Pan-NOX Inhibitors (Including Those with More-Focused Selectivity)
5.1 Celastrol
6 NOX1
6.1 Setanaxib and other GKT Derivatives
6.2 ML171 and ML090
6.3 NOS31
6.4 NOXA1ds
6.5 NF02
7 NOX2
7.1 NOX2ds-tat
7.2 GSK2795039
7.3 CYR5099
7.4 PHOX-I1 and PHOX-I2
7.5 Ebselen
7.6 Perhexiline
7.7 Naloxone
7.8 CPP11G and CPP11H
7.9 Other Potential NOX2 Inhibitors
8 NOX4
8.1 Setanaxib and other GKT Derivatives
8.2 GLX351322, GLX481372, GLX7013114, and GLX481304
8.3 ACD042(Grindelic Acid) and ACD084
8.4 Fulvene-5
8.5 NOX4 Inhibitors in the Pipeline
9 NOX5
9.1 Peptide Inhibitors of NOX5
9.2 ML090
9.3 Gedunin
10 DUOX1 and DUOX2
11 Conclusions and Perspectives: Is There a Need for Isoform-Specific NOX Inhibitors?
References
22: Proteins Cross-talking with Nox Complexes: The Social Life of Noxes
1 Associated Proteins with a Main Stimulatory Effect on Noxes
1.1 Kinase-Related Nox Organizers
1.2 General Nox Organizers
1.3 Chaperone-Like Nox Agonists
1.4 RhoGTPase and/or Cytoskeleton-Related Nox Organizers
1.5 Scaffold Proteins Supportive of Nox Activation
2 Associated Proteins with a Main Inhibitory/Mixed Effect on Noxes
2.1 Kinase-Related
2.2 Chaperone-Like
2.3 RHOGTPase and/or Cytoskeleton-Related
3 Concluding Remarks
References
Part V: Non-Mammalian NADPH Oxidases
23: NADPH Oxidase-Dependent Processes in the Social Amoeba Dictyostelium discoideum
1 Introduction
2 The Model Organism Dictyostelium discoideum
3 The Amoebal Repertoire of NADPH Oxidases
3.1 Dictyostelium Genome Encodes 3 Members of the NOX Family: NoxA, NoxB and NoxC
3.2 Dd-CybA, the Amoebal Homolog of the p22phox Subunit
3.3 A Limited Repertoire of Cytosolic Factors
3.4 NADPH Oxidase Components Are Differentially Expressed During Development
3.5 ROS Production and Dictyostelium NOXs
4 Roles for NADPH Oxidases in Dictyostelium Organism
4.1 Involvement of NADPH Oxidases in Dictyostelium Development
4.2 Involvement in Intraphagosomal Processing of Microbes
4.3 A Role in S-Cell Mediated Innate Immunity
5 Conclusion
References
24: Discovery and Functional Analysis of the Single-Celled Yeast NADPH Oxidase, Yno1
1 Introduction
2 History of the Discovery of Yno1
3 The Interaction of Yno1 with Sod1 Produces H2O2 as a Signaling Molecule
4 Interaction of Yno1 with the Yeast Ras2 Signaling System
5 Definition of the YNO1 Subfamily of Yeast NADPH Oxidases in Relation to the Structure and Mechanism of Other NADPH Oxidases ...
6 The Interaction of Yno1 Signaling with the Actin Cytoskeleton of the Yeast Cell
7 Studies of Gene Expression of YNO1 in Relation to Filamentous Growth, Mating, and the Osmotic Stress Response
8 Conclusions: A Model for Yno1 Functions
References
25: NADPH Oxidases in Fungi
1 Introduction
2 Role of Nox in Fruiting Body Development and Ascospore Germination
3 Nox Controlled Differentiations Associated with Plant Pathogenesis and Symbiosis
4 Other Differentiations
5 Structure of Fungal NADPH Oxidases
6 Activation Mechanism of Fungal NADPH Oxidases
7 Distribution of NoxA, NoxB, NoxC and Predicted Regulatory Components of Fungal NADPH Oxidases
8 Conclusions
Glossary
References
26: Plant NADPH Oxidases
1 Introduction
2 The Discovery of Plant NOXs
3 Structure of RBOH Proteins
3.1 Regulation of Activation
4 Cellular Distribution of RBOH Proteins
5 RBOH Gene Expression
5.1 Biological Function
5.1.1 Tissue Specific Function of RBOHs
Roots
Lateral Roots (LRs)
Root Hair Elongation
Pollen Fertility
Seeds Germination
6 Involvement in Stress Responses
7 Role in Plant Immunity
8 Role in Stomata Closing
9 Role in Cell-to-Cell Signaling and Systemic Responses
10 Conclusions
References
27: Nematode Noxes: The DUOXes of Caenorhabditis elegans
1 Introduction
2 Structural Characteristics and Expression
2.1 Structural Features
2.2 Expression and Tissue Distribution
3 Biological Roles
3.1 Roles in Development
3.1.1 Cuticle
3.1.2 Vulva
3.2 Roles in Immunity
3.3 Roles in Aging
3.4 Roles in Stress Resistance
4 Regulators
4.1 Tetraspanin/DUOXA Activating Complex
4.2 Small G-Proteins
4.2.1 CED-10
4.2.2 MEMO-1/RHO-1
5 Functional Interactors: Peroxidases
5.1 MLT-7
5.2 SKPO-1
5.3 HPX-2
6 Conclusions
References
28: NADPH Oxidases in Arthropods
1 Introduction
2 DUOX
2.1 Immune System
2.1.1 Arachnida
2.1.2 Crustacea
2.1.3 Lepidoptera
2.1.4 Diptera
2.2 Tissue Regeneration
2.3 Cuticle Stabilization
2.4 Other Functions
3 NOX5
3.1 Immune System
3.1.1 Arachnida
3.1.2 Crustacea
3.1.3 Lepidoptera
3.1.4 Diptera
3.2 Contraction
3.3 Tissue Regeneration
3.4 Other Functions
4 NOX4-art
5 NOX Evolution
6 Conclusion
References
29: NADPH Oxidases in Zebrafish
1 Introduction
2 Zebrafish as a Model System: A Historical Perspective
3 Zebrafish as a Model System to Investigate NADPH Oxidases and ROS
4 Expression of NADPH Oxidases in Zebrafish
5 Biological Functions Regulated by NADPH Oxidases in Zebrafish
5.1 Nox in Zebrafish Development
5.2 Nox in Zebrafish Wound Healing and Regeneration
5.3 Nox in Antimicrobial Defense in Zebrafish
5.4 Nox in Zebrafish Tumorigenesis
5.5 Nox in Zebrafish Circadian Clock
6 Conclusion
References
Part VI: Structure
30: Structural Insights into the Mechanism of DUOX1-DUOXA1 Complex
1 Introduction
2 Architecture of DUOX1 and DUOXA1
3 Interdomain Interaction and DUOX1-DUOXA1 Complex Architecture
4 Substrate and Cofactor Binding Sites for NADPH, FAD, Heme, and Oxygen
5 Electron Transfer Pathway
6 Activation and Modulation
7 Perspective
References
31: Structure, Function and Mechanism of Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) Enzymes
1 Identification of STEAPs as Transmembrane Oxidoreductases
2 STEAPs in Metabolic Homeostasis
3 STEAPs Are Overexpressed in Cancer and Represent Potential Therapeutic Targets
4 STEAPs Enable Transmembrane Electron Transport Through an Array of Cofactors
4.1 Hydride Transfer Between NADPH and FAD
4.2 Electron Transport Across the Membrane from FAD to Heme
4.3 Metal Ion Reduction
5 The Elusive Cellular Function of STEAP1
6 STEAPs Share a Common Transmembrane Architecture with NOX Enzymes
7 Outlook
References
Part VII: Pathology
32: Chronic Granulomatous Disease
1 Introduction
2 Clinical Aspects
2.1 Symptoms and Infecting Microorganisms
2.2 Treatment of Infections and Hyperinflammation in CGD
3 Cellular Aspects
3.1 Intraphagosomal and Extracellular ROS Production Are Deficient in CGD Patients
3.2 NADPH Oxidase Activity Can Be Stimulated by Soluble Activators
3.3 CGD Diagnosis: ROS Measurement in CGD Neutrophils
3.4 Cellular Models Used to Improve Our Knowledge of NADPH Oxidase Functioning and for the Development of New Therapies for CGD
4 Genetic Aspects
4.1 Genes and Mutations
4.2 Genetic Diagnosis
4.3 Relation Between Mutations and Disease Severity
5 Future Developments
References
33: Definitive Treatments for Chronic Granulomatous Disease with a Focus on Gene Therapy
1 Introduction
1.1 Hematopoietic Stem Cell Transplantation
1.2 Gene Therapy
1.2.1 Conventional Gene Therapy
1.2.2 Gene Editing
2 Hematopoietic Stem Cell Transplantation for CGD
3 Gene Therapy for CGD
3.1 Early Trials
3.2 New, Myeloid-Specific Vectors for the Gene Therapy of CGD
3.3 Gene Therapy for CGD: The Present
3.4 Clinical Success: Are We There Yet?
3.5 New Platforms: Gene Editing for CGD
4 Concluding Remarks
References
Part VIII: Future
34: Quo Vadis NADPH Oxidases: Perspectives on Clinical Translation
1 Introduction
2 Structure, Expression and Activity of NADPH Oxidases
3 The Complexity of NOXs as Therapeutic Targets
3.1 Intracellular Signaling Related to NOXs
4 NADPH Oxidase Animal Models
4.1 Limitations of Animal Models
4.1.1 Disease Complexity
4.1.2 Biological Dynamicity and Contextuality
4.1.3 Aging and Antagonistic Pleiotropy
4.2 Strategies to de-Risk Evaluation of NOX/DUOX as a Drug Target
5 NADPH Oxidase-Disease Linkage
5.1 NADPH Oxidases in Immunity
5.2 NADPH Oxidases in Organ Fibrosis
5.3 NADPH Oxidases in Cardiovascular Disease
6 Conclusions
References
Index
