Sphingolipid Biology (eBook)

Foreword 5
Contents 7
Contributors 12
Part 1 Overview 26
1-1 Sphingolipids Synthesis, Transport and Cellular Signaling 27
1. Introduction 28
2. Structures and nomenclature 28
3. Biologic functions 33
4. Sphingolipid metabolism 36
5. Integration of sphingolipid biosynthesis with membrane trafficking, organelle function and signaling 39
6. Emerging areas and perspectives for the future 42
7. Looking to the future with the wisdom of the past 45
8. References 45
Part 2 Biosynthesis, Transport of Sphingolipids 47
2-1 Serine Palmitoyltransferase 48
1. Introduction 48
2. Biochemical and genetic characteristics of SPT 49
3. Regulation of serine palmitoyltransferase 56
4. Functional significance of SPT in health and disease 60
5. Future directions 63
6. References 63
2-2 Ceramide Synthase 71
2-3 Dihydroceramide'Sphinganine h4-Desaturase and C4-Hydroxylase 79
1. Introduction 79
2. & 4-Desaturase
3. C4-Hydroxylase 82
4. Yeast C4-hydroxylase 85
5. Phylogenetic aspects of DES1 and 2 86
6. Molecular mechanisms of A4-desaturation and C4-hydroxylation 87
7. DES1 and DES2 knockout experiments 88
8. References 88
2-4 Metabolizing Enzymes Such As Sphingomyelin Synthase Induce Cell Death by Increasing Ceramide Content 91
1. Introduction 92
2. Ceramide in cell death and growth/survival 92
3. SMS in hematological malignancy 94
4. Cloning of cDNA for SMS and its implication in Fas-induced cell death 97
5. Involvement of ceramide in angiogenesis in zebrafish 100
6. Concluding remarks 101
7. References 102
2-5 Glucosylceramide and Galactosylceramide Synthase 104
1. Introduction 104
2. Glucosylceramide synthase 106
3. Galactosylceramide synthase 110
4. References 112
2-6 Synthesis, Metabolism, and Trans-Bilayer Movement of Long-Chain Base 116
1. Introduction 116
2. Production of LCBs 117
3. LCB metabolism 120
4. Trans-bilayer movement of LCB 122
5. Future directions 123
2-7 Molecular Mechanism of Ceramide Trafficking from the Endoplasmic Reticulum to the Golgi Apparatus in Mammalian Cells 128
1. Introduction 128
2. Biosynthesis and translocation of sphingolipids in mammalian cells 129
3. LY-A, a mammalian cell mutant defective in intracellular trafficking of ceramide 130
4. Reconstitution of ceramide trafficking in semi-intact CHO cells 131
5. Molecular cloning of CERT, the factor impaired in LY-A cells 132
6. CERT inhibitor 136
7. Model of molecular mechanisms of ceramide trafficking 136
8. CERT and Goodpasture antigen-binding protein (GPBP) 138
9. References 139
2-8 Sphingolipid Trafficking 143
1. Introduction 143
2. Movement of sphingolipids between the two leaflets of ER membrane 144
3. Transport of sphingolipids between the ER and the Golgi 146
4. Intra-Golgi transport of sphingolipids 149
5. Transport of sphingolipids from the Golgi complex to the PM 150
6. Endocytosis and sorting of sphingolipids 152
7. Perspectives 153
8. References 154
2-9 Current Perspectives on Saccharomyces cerevisiae Sphingolipids 160
1. Introduction 160
2. Sphingolipid metabolism in S. cerevisiae 161
3. Signaling pathways regulated by LCBs 162
4. Future directions 166
5. References 166
Part 3 Generation and Degradation of Sphingolipid Signaling Molecules 170
3-1 Generation of Signaling Molecules by De Novo Sphingolipid Synthesis 171
1. Introduction 171
2. De novo sphingolipid metabolism 172
3. Distinguishing salvage from de novo sphingolipid synthesis 174
4. Mechanisms of regulation of de novo sphingolipid synthesis 174
5. Contributions of de novo sphingolipid synthesis to biology 176
6. Conclusions 178
7. References 178
3-2 Overview of Acid and Neutral Sphingomyelinases in Cell Signaling 184
1. Introduction 184
2. Acid sphingomyelinase 185
3. Neutral Mg2*-dependent sphingomyelinases 188
4. Future directions 192
5. References 193
3-3 Neutral Ceramidase as an Integral Modulator for the Generation of $1P and $1 P-Mediated Signaling 199
1. Introduction 200
2. Intracellular distribution and topology of neutral CDase 201
3. A function of the evolutionary-acquired mucin-like domain of neutral CDase 204
4. Involvement of a plasma membrane-bound neutral CDase and a secreted neutral CDase in the generation of Sph and SIP 205
5. Involvement of neutral CDase in $1 P-mediated angiogenesis during zebrafish embryogenesis 208
6. References 209
3-4 Activation of Sphingosine Kinase 1 213
1. Functions of SIP 213
2. The kinases that produce $1 P 214
3. Regulation of SphK1 by post-translational modifications 215
4. Regulation of SphK1 expression 216
5. Regulation of SphK1 by interaction with lipids 217
6. Regulation of SphK1 by interaction with proteins 217
7. References 220
3-5 Ceramide 1-Phosphate 223
1. Introduction 223
2. Ceramide kinase 224
3. Physiological role of CERK and C1P 227
4. CERK/CIP related enzymes 228
5. References 231
3-6 Sphingosine-l-Phosphate Lyase 235
1. Introduction 236
2. Enzyme properties, subcellular localization and topology 238
3. SPL-encoding genes 239
4. Expression patterns and gene regulation 240
5. SPL in biology and disease 241
6. Conclusions and future directions 243
7. References 243
Part 4 Membrane Domain and Biological Function 247
4-1 Close Interrelationship of Sphingomyelinase and Caveolin in Triton X-lOO-Insoluble Membrane Microdomains 248
1. Introduction 249
2. Co-existence of SMases and caveolins in microdomains of cell membrane 249
3. Conclusion 256
4. References 257
4-2 Roles of Membrane Domains in the Signaling Pathway for B Cell Survival 260
1. Proliferation and differentiation of B cells depends on antigen recognition 261
2. Involvement of membrane domains in the signaling pathway for B cell survival 261
3. B cell survival signals induced by an agonistic antibody CS/2 is similar to BCR-crosslinking 262
4. A possible involvement of lipid-mediated signaling for CS/2-dependent B cell survival 263
5. References 265
4-3 The Role of Lipid Rafts in Axon Growth and Guidance 267
1. Introduction 267
2. Axon growth 268
3. Axon guidance 272
4. Conclusion 272
5. References 273
4-4 Sphingolipids and Multidrug Resistance of Cancer Cells 276
1. Multidrug resistance 276
2. Sphingolipids and growth control 277
3. Sphingolipids and multidrug transporters 279
4. Sphingolipids and multidrug resistance 281
5. References 281
Part 5 Membrane Lipid Domain and Human Pathobiology 284
5-1 A New Pathological Feature of Insulin Resistance and Type 2 Diabetes" Involvement of Ganglioside GM3 and Membrane Microdomains 285
1. Introduction 286
2. Effects of TNF~ and D-PDMP on Insulin Signaling through IR to IRS-1 287
3. Enhanced Expression of GM3 Synthase mRNA in Adipose Tissues from Typical Rodent Models with Insulin Resistance 288
4. IR is a component of DRMs and is selectively eliminated during insulin resistance induced by TNF(~ 289
5. GSL depletion attenuates TNF¢-induced inhibition of insulin-stimulated IR internalization and dissociation of IR from DRMs 290
6. Discussion 291
7. References 293
5-2 Neuronal Cell Death in G lycosph i ngoli pidoses 297
1. Clinical description of the GSDs 297
2. Neuronal cell dysfunction and death in GSDs 298
3. Other potential pathological mechanisms 301
4. References 302
5-3 Endocytic Trafficking of Glycosphingolipids in Sphingolipidoses 306
1. Introduction 307
2. Endocytic itinerary of GSLs (Fig. 1) 308
3. Perturbation of the function of selected Rab GTPases by cholesterol 312
4. Rab over-expression and correction of the SLSD phenotype 315
5. References 316
5-4 Ganglioside and Alzheimer's Disease 319
1. Introduction 319
2. Identification of ganglioside-bound form of AB in human and monkey brains 320
3. GAB scaffolding for AB aggregation 320
4. Validation of GAB generation in human and monkey brains 322
5. Putative molecular mechanisms underling GAB generation 324
6. Pathological implications of risk factors for AD to GAB generation 324
7. Pivotal role of ganglioside in brain-region-specific assembly and AB deposition 325
8. Conclusions 326
9. References 326
5-5 Modulation of Proteolytic Processing by Glycosphingolipids Generates Amyloid B-Peptide 328
1. Introduction 329
2. Results 330
3. Discussion 334
4. References 335
5-6 Hereditary Sensory Neuropathy 338
1. Many gene defects (mutations) cause hereditary neuropathies 339
2. Hereditary Sensory Neuropathy type I 339
3. Discovery of the HSN1 gene mutations 340
4. Rationale for exploring mechanisms of distal axonopathy 340
5. Do the mutations affect SPT activity? 341
6. Protein instability, aggregation and interference with protein trafficking 342
7. Final Remarks 343
8. References 343
5-7 Ceramide, Ceramide Kinase and Vision Defects" A BLIND Spot for LIPIDS 345
5-8 Fumonisin Inhibition of Ceramide Synthase" A Possible Risk Factor for Human Neural Tube Defects 353
1. Introduction 354
2. Fumonisin inhibition of ceramide synthase and folate transport 355
3. NTDs in mouse models, folate and sphingolipids 359
4. NTDs in humans, maize consumption and fumonisin exposure 362
5. References 364
5-9 Sphingolipids and Cancer 370
1. Introduction 370
2. Cancer development- multiple stages that can be targeted by sphingolipids 371
3. Targeting enzymes of the sphingolipid Metabolism for cancer prevention and treatment 374
4. The future of sphingolipids in cancer prevention and treatment 380
5. References 381
Part 6 S1P Signaling and SIPR 389
6-1 Sphingosine-l-Phosphate and the Regulation of Immune Cell Trafficking 390
1. Generation of $1 P 391
2. $1P family of receptors 391
3. $1 P is a normal component of circulating blood and acutely released during inflammation 392
4. Immune cells express SIP receptors and are regulated by SIP 393
5. Insights from Pharmacology 397
6. Insights from Genetics 398
7. Conclusions and perspectives 400
8. References 400
6-2 Sphingolipids and Lung Vascular Barrier Regulation 408
1. Overview of vascular barrier regulation 408
2. Sphingolipids and endothelial cell biology 410
3. In vitro alterations in the cytoskeleton, monolayer integrity, and angiogenesis 412
4. In vivo applications of sphingolipids: injury and ischemia/reperfusion injury acute lung 414
5. References 417
6-3 Signaling Mechanisms for Positive and Negative Regulation of Cell Motility by Sphingosine-l-Phosphate Receptors 420
1. Introduction 421
2. Receptor subtype-specific, bimodal regulation of cell motility and the small GTPase Rac by $1 P 422
3. Stimulation and inhibition of melanoma cell invasion and metastasis by SIP receptors 425
4. Differential regulation of Rac and cell migration by endogenous Edg receptors in vascular smooth muscle and endothelial cells 427
5. Future directions 428
6. References 429
6-4 Sphingosine 1-Phosphate-Related Metabolism in the Blood Vessel 431
1. Introduction 432
2. SIP release from activated platelets: source of plasma SIP 432
3. The source of Sph for SIP production in platelets 435
4. SIP is a normal constituent of human plasma and serum 437
5. Regulation of SIP plasma levels by LPPs 438
6. Concluding remarks 439
7. References 439
Part 7 Advanced Technology in Sphingolipid Biology 444
7-1 Conventional/Conditional Knockout Mice 445
1. Structure and biosynthesis of sphingolipid 446
2. Study of sphingolipid function using cell lines 446
3. Study of sphingolipid function using genetically altered mice 447
3.3 Conditional knockout by disruption of the Sptlc2 gene 449
4. Current progress in the study of sphingolipid function using gene-modified mice 450
5. References 451
7-2 Biosynthesis and Function of Drosophila Glycosphingolipids 454
1. Introduction: Drosophila is a powerful model organism for analyzing sphingolipids 454
2. Glycosphingolipid pathway in Drosophila 456
3. Glucosylceramide synthase (GIcT-1/GCS/UGCG) 457
4. Egghead (egh) and brainiac (brn) define lipid glycosyltransferase functions 459
5. Conclusion 460
6. References 460
7-3 Characterization of Genes Conferring Resistance Against ISP-1/Myriocin-lnduced Sphingolipid Depletion in Yeast 463
1. Introduction 463
2. Action of ISP-1 and isolation of ISP-1 resistance genes in yeast 466
3. Conclusion 470
4. References 471
7-4 Lysenin" A New Probe for Sphingomyelin 475
1. Introduction 475
2. Lysenin recognizes sphingomyelin in distribution- dependent manner 476
3. Lysenin is a pore-forming toxin 477
4. Non-toxic lysenin reveals spatial and functional heterogeneity of sphingolipid-containing membrane domains 479
5. Perspectives 480
6. References 481
7-5 Structural Biology of Sphingolipid Synthesis 483
1. Introduction 484
2. Cloning, overproduction, purification and characterization of bacterial SPTs 484
3. Structure of a bacterial SPT 488
4. References 490
7-6 A Computer Visualization Model for the De Novo Sphingolipid Biosynthetic Pathway 493
1. Introduction 493
2. Design and development of visualization system 497
3. SphingoViz functionalities 501
4. Conclusion 506
5. References 506
Appendix 509
I. Inhibitors of Sphingolipid Biosynthesis 510
II. The Genes in Yeast and Mammals 513
III. Structure of Glycosphingolipids and Metabolic Pathway 516
Keyword Index 526