Sphingolipids as Signaling and Regulatory Molecules (eBook)

CHARLES CHALFANT is a tenured Associate Professor of Biochemistry and Molecular Biology at Virginia Commonwealth University-School of Medicine. He is also a Research Career Scientist in the Veterans Administration based at the Hunter Holmes McGuire Veterans Administration Medical Center in Richmond, Virginia. His main research interests lie in lipid signaling, specifically the role of intracellular lipid second messengers (e.g., ceramide-1-phosphate) in regulating eicosanoid synthesis. He also studies the role of oncogenic signaling pathways in regulating the alternative splicing of tumor suppressor genes such as caspase 9. Dr. Chalfant serves on the Editorial Board of The Journal of Lipid Research as well as on several National Panels of Scientific Review including formal membership on the Cancer Molecular Pathobiology Study Section for the National Institutes of Health and the Oncology A Study Section for the Veterans Administration. He received his PhD degree from the University of South Florida-College of Medicine and did his postdoctoral studies at Duke University and the Medical University of South Carolina. MAURIZIO DEL POETA , MD is a tenured Associate Professor of Biochemistry and Molecular Biology, Microbiology and Immunology, Craniofacial Biology, and for the Division of Infectious Diseases at the Medical University of South Carolina, Charleston, South Carolina, USA. He is also the Director of the Graduate Program in Biochemistry and Molecular Biology at MUSC. Main research interests include the study of the role of sphingolipids in fungal pathogenesis and the development of new diagnostic and therapeutic strategies against fungal infections. He received many awards for his research discoveries and teaching. He is also a member of many national and international societies such as the American Society for Clinical Investigation (ASCI), the American Society for Biochemistry and Molecular Biology, and the American Society for Microbiology. Dr. Del Poeta is a Burroughs Wellcome New Investigator in the Pathogenesis of Infectious Diseases.

Copyright Page 5
DEDICATION 6
PREFACE 7
ABOUT THE EDITORS... 8
ABOUT THE EDITORS... 9
PARTICIPANTS 10
Table of Contents 15
ACKNOWLEDGEMENTS 21
Chapter 1 An Overview of SphingolipidMetabolism:From Synthesis to Breakdown 22
Sphingolipid Properties in Membranes 23
De Novo Synthesis in the ER 24
Serine Palmitoyltransferase and 3-Ketodihydrosphingosine Reductase 25
Dihydroceramide Synthases/Ceramide Synthases and Dihydroceramide Desaturase 26
Ceramide Transport from the ER to the Golgi 27
Synthesis of Complex Sphingolipids 28
Ceramide Galactosyltransferase and Galactosphingolipids 28
Glucosylceramide Synthase and Derivatives of Glucosylceramide 29
Sphingomyelin Synthesis 29
Ceramide Kinase and Ceramide-1-Phosphate 30
Catabolizing Complex Sphingolipids and Sphingomyelins into Ceramide 31
The Catabolism of Ceramides and the Final Common Breakdown Pathway 33
Acid, Neutral and Alkaline Ceramidases 33
Sphingosine-1-Phosphate and Sphingosine Kinases 1 and 2 35
Lipid Phosphate Phosphatases, S1P Phosphatases and the Salvage Pathway 36
S1P Lyase in the Removal of Sphingoid Bases 37
Conclusion 38
References 38
Chapter 2 Sphingolipid Transport 45
Introduction 45
Intramembrane Sphingolipid Movements 46
Lateral Diffusion and Lateral Phase Separation of Sphingolipids 46
Sphingolipid Raft Dynamics 47
Transbilayer Transport 48
Transbilayer Transfer of Sphingomyelin and Complex Glycosphingolipids 49
Transbilayer Transfer of Monohexosylsphingolipids 52
Transbilayer Transfer of Ceramide and Sphingoid Bases 52
Transbilayer Transfer of Sphingosine-1-Phosphate 53
Intermembrane Sphingolipid Transport 53
Protein-Mediated Sphingolipid Transport 54
CERT-Mediated Transport of Ceramides 54
FAPP2-Mediated Transport of Glucosylceramide 57
Glycolipid Transfer Proteins 57
Membrane Contacts 58
Sphingolipid Vesicular Transport 58
Biosynthetic Vesicular Pathway 58
Endocytic Pathway 59
Conclusion 60
References 61
Chapter 3 Sphingolipid Analysisby High Performance LiquidChromatography-Tandem MassSpectrometry (HPLC-MS/MS) 67
Introduction 67
Sphingolipids: Structure and Composition 68
LC-MS Methods for Detection and Analysis of Bioactive Sphingolipids 70
Lipidomic Approach 70
Sample Preparation 70
Analysis of Intact Sphingolipids by Mass Spectrometry 71
Mechanism of Electrospray Ionization Mass Spectrometry (ESI/MS) 72
MS Scan Modes 72
Specific Scan Modes for MS/MS Instrumentation 73
Product Ion Scan 73
Neutral Loss (NL) 73
Precursor Ion Scan (PI) 73
Multiple Reaction Monitoring (MRM) 73
Sphingolipid Identification 73
HPLC-MS/MS Methodology 74
Quantitation 75
Selection of Internal Standards (ISs) 76
Quantitative Calibration 76
Data Handling 76
Alternative Methodology 77
Conclusion 77
References 77
Chapter 4 Ceramide Synthases:Roles in Cell Physiology and Signaling 81
Introduction 81
Fatty Acid Specificity, Kinetics and Tissue Distribution 83
Inhibitors 84
Fumonisins 84
Australifungin 85
FTY720 85
Posttranslational Modifications 85
Membrane Topology 85
Why Are There So Many Mammalian CerS? 87
Roles of CerS in Signal Transduction and Disease 88
Conclusion 89
References 89
Chapter 5 Tales and Mysteries of the EnigmaticSphingomyelin Synthase Family 93
Sphingomyelin Biosynthesis: An Historical Perspective 93
Initial Milestones 93
Localization of SM Synthase Activity in Cells 94
Discovery of a Ceramide Transfer Protein with a Key Role in SM Biosynthesis 96
Alternative Pathways of SM Biosynthesis and Analogous Reactions 96
Physicochemical Properties of SM 97
The Multigenic Sphingomyelin Synthase (SMS) Family 97
SMS Cloning Strategies 97
Structural Organization and Reaction Chemistry of SMS Family Members 98
SMS Family Members Display Striking Variations in Substrate Specificity 99
Differential Expression of SMS1 and SMS2 100
Cellular Functions of SMS Family Members 100
SMS1 and SMS2 as Regulators of SM Homeostasis and Receptor-Mediated Signaling 100
SMS1 and SMS2 as Regulators of Lipid-Based Signaling 101
Conclusion 102
References 103
Chapter 6 Ceramide in Stress Response 107
Introduction 107
Chemical Structure and Biophysical Properties of Ceramide 108
Changes in Ceramide Mass during Stress 108
Mechanisms for Ceramide Generation during Stress 112
Role of the De Novo Pathway for Ceramide Generation in Cellular Stress Response 112
Heat Stress 113
Septic Shock 113
Lipotoxicity and Insulin Desensitization 114
Programmed Cell Death 114
Autophagy 115
Mechanisms of Activation of De Novo Synthesis of Ceramide during Stress 115
Role of the Sphingomyelinases in Cellular Stress Response 115
Neutral Sphingomyelinase 116
Hepatic Acute Phase Response 116
Vascular Inflammation 116
Apoptosis 116
Growth Arrest 116
Aging and Cancer 117
Mechanisms of Activation of NSMase 117
Acid Sphingomyelinase 118
Endotoxic Shock 118
Apoptosis (reviewed in ref. 162) 118
Viral and Bacterial Infections 118
Mechanisms of Activation of ASMase 118
Evidence for a Coordinated Regulation of Multiple Pathways for Ceramide Generation 118
Mechanisms of Ceramide Effects on Cellular Functions 119
Ceramide-Interacting Molecules 119
PKC (reviewed in ref. 114) 119
PP2A (reviewed in ref. 181) 119
Cathepsin D 119
Indirect Targets of Ceramide 120
Modulators of Apoptosis (reviewed in ref. 184) 120
Regulators of Cell Cycle 120
Regulators of Inflammation 120
Ceramide Effects on Membrane Organization 121
Conclusion 121
References 122
Chapter 7 Animal Models for Studyingthe Pathophysiology of Ceramide 130
Introduction 130
Sphingosine Kinase 1/2 130
Ceramidases 131
Acid Ceramidase 131
Neutral Ceramidase 132
Sphingomyelinases (SMase) and Sphingomyelin Synthases (SMS) 132
Acid Sphingomyelinase (ASMase) 132
Neutral Sphingomyelinase (nSMase) 1/2 133
Sphingomyelin Synthases (SMS) 133
S1P Lyase 133
The Other GEM for Sphingolipid-Related Enzymes 134
Conclusion 134
References 135
Chapter 8 Ceramide-1-Phosphate in Cell Survivaland Inflammatory Signaling 139
Introduction 139
Ceramide-1-Phosphate Synthesis and Degradation 140
Ceramide-1-Phosphate: A Key Regulator of Cell Growth and Survival 142
Ceramide-1-Phosphate and the Control of Inflammatory Responses 144
Ceramide-1-Phosphate Mediates Macrophage Migration 145
Conclusion 146
References 147
Chapter 9 Ceramide-1-Phosphate in Phagocytosisand Calcium Homeostasis 152
Ceramide-1-Phosphate in Phagocytosis 152
Ceramide-1-Phosphate as a Regulator of Calcium Homeostasis 155
Conclusion 158
References 159
Chapter 10 Extracellular and Intracellular Actionsof Sphingosine-1-Phosphate 162
Introduction 162
Sphingolipid Metabolism 162
Sphingosine Kinases 163
SphK1 164
SphK2 164
SphK1 vs. SphK2 164
S1P Receptors 166
S1P1 166
S1P2 167
S1P3 167
S1P4 and S1P5 167
Evidence for Intracellular Targets of S1P 168
S1P in Saccharomyces cerevisiae 168
S1P in Arabidopsis thaliana 168
S1P in Mammalian Cells 169
Implications, Future Directions, and Conclusion 171
References 171
Chapter 11 Glucosylceramide in Humans 177
Introduction 177
Glucosylceramide Synthesis and Degradation 177
Multiple Functions of Glucosylceramide 179
Template for Higher Order Glycosphingolipids 179
Membrane and Lipid Raft Constituent 179
Cellular Protection in the Skin 180
Cellular Protection in the Cardiovasculature 180
Cellular Protection in the Brain 181
Cellular Protection in the Immune System 181
Cellular Protection in Carcinomas 182
Conclusion 182
References 183
Chapter 12 Gangliosides as Regulators of CellMembrane Organization and Functions 186
Introduction 186
Segregation of Membrane Lipids and Detergent-Resistant Membrane Domains 190
Lipid Membrane Domain Functions 192
Gangliosides and Lipid Membrane Domains in the Nervous System 192
The Glycosynapse 193
GM3 and EGF Receptor 194
GM3, Caveolae and the Regulation of Insulin Receptor and PDGF Receptor 195
The Regulation of Glycosphingolipid Composition of the Plasma Membranes 195
Conclusion 197
References 197
Chapter 13 Cancer Treatment Strategies TargetingSphingolipid Metabolism 206
Introduction 206
Sphingolipid Metabolism 207
Ceramide Generated via Different Biochemical Routes Can Induce Apoptosis 208
Ceramide as a Mediator of Cell Death by Chemopreventive Agents 209
Ceramide Influences Both the Intrinsic and Extrinsic Apoptotic Pathways 209
Sphingosine-1-Phosphate as a Counterbalance to Ceramide 210
Inhibitory Effects of S1P on Apoptotic Pathways 211
Sphingolipids Regulate Key Signaling Pathways That Control Cell Fate 211
Sphingolipids and Autophagy 213
Other Signaling Pathways Influenced by Sphingolipids 214
Ceramide Regulates Cell Cycle Progression 214
Ceramide and Telomerases 215
Ceramide and S1P in Cancer Stem Cells 215
Effects of S1P on Migration and Metastasis 215
Cancer Cells Exhibit Molecular and Genetic Changes in Sphingolipid Metabolism 215
Targeting Sphingolipids for Cancer Therapy 217
S1P Signaling to Protect Normal Tissues from Therapy-Related Cytotoxicity 219
Conclusion 219
References 219
Chapter 14 Therapeutic Strategies for Diabetesand Complications:A Role for Sphingolipids? 227
Diabetes and Insulin Resistance 227
Insulin Resistance and Altered Sphingolipid Metabolism 228
Diabetic Pancreatic Dysfunction and Sphingolipids 230
Diabetic Cardiovascular Dysfunction and Sphingolipids 230
Diabetic Nephropathy and Sphingolipids 231
Diabetic Retinopathy and Sphingolipids 231
Therapeutics That Target Sphingolipid Metabolism or Sphingolipid Signaling in Diabetes 232
Conclusion 233
References 234
Chapter 15 Roles for Sphingolipidsin Saccharomyces cerevisiae 238
Introduction 238
Sphingolipid Metabolism in S. cerevisiae 238
Membrane-Associated Functions and Processes 240
Signal Transduction Pathways That Require Sphingolipids 243
Longevity and Cellular Aging 245
Regulation of Sphingolipid Biosynthesis 246
Conclusion and Future Developments 247
References 248
Chapter 16 Sphingolipid Signaling in FungalPathogens 253
Sphingolipid Synthesis 253
Cryptococcus Neofomans: Model of Sphingolipid Signaling in Fungi 254
Sphingolipid Signaling in Other Pathogenic Fungi 256
Conclusion 256
References 257
Chapter 17 Sphingolipids in Parasitic Protozoa 259
Introduction 259
Leishmania 259
SL Pathway Genetics 261
SL Salvage by Amastigotes 261
Inhibition of SL Synthetic Pathways 262
Trypanosoma brucei (ssp) and Trypanosoma cruzi 262
Trypanosoma brucei 262
Trypanosoma cruzi 263
Trypanosomatid Sphingolipid Synthases 264
Plasmodium falciparum 265
Toxoplasma gondii 265
Trichomonas vaginalis and Giardia lamblia 266
Conclusion 266
References 267
Chapter 18 Biosynthesis of Sphingolipids in Plants(and Some of Their Functions) 270
Introduction 270
Pathway of Plant Sphingolipid Biosynthesis 271
Functional Characterization of Genes and Enzymes Involved in Plant Sphingolipid Biosynthesis (2004-2008) 276
Serine Palmitoyltransferases 276
Long-Chain Base C4-Hydroxylases 277
Ceramidase 277
Fatty Acyl a-Hydroxylase 277
Sphingolipid- 4(E)-Desaturase 278
Sphingolipid- 8(E/Z)-Desaturases 278
Inositolphosphorylceramide Synthase (IPCS) 278
Long-Chain Base Kinase and Long-Chain Base Phosphate Phosphatase 279
Long-Chain Base Phosphate Lyase 281
Conclusion 281
References 282
Chapter 19 Computational Analysis of SphingolipidPathway Systems 285
Introduction 285
Sphingolipid Models and Their Potential Uses 289
Conclusion 294
References 295
Appendix Introduction to Tools and Techniquesfor Ceramide-Centered Research 297
Lipid Extraction 297
Identification and Quantification of Steady State Levels of Ceramide 297
Analysis of Ceramide Metabolism 299
The Use of Ceramide Analogues 300
Short-Chain Ceramides 300
Fluorescent Ceramide Analogues 300
Pharmacological Tools 300
Genetic Tools 300
RNA Interference 300
Knockout Mice 300
Conclusion 303
References 303
Index 307