Beat Ernst Gerald W. Hart Pierre Sinay

CarbohydratesIn Chemistryand Biology

Part II

Biology of Saccharides

Vol . 3

Biosynthesis and Degradationof Glycoconjugates

Part II Biology of Saccharides

Vol. 3

Biosynthesis and Degradation of Glycoconjugate s

Introduction to Volumes 3 and 4 V

Abbreviations Used in Volumes 3 and 4 LV

I

Biosynthesis of Glycoconjugates 1

1

Metabolism of Sugars and Sugar Nucleotides 3Hudson H. Freeze

1 .1

Introduction 31 .2

Basic Principles 31 .3

Transporters Deliver Monosaccharides to Cells 41 .4

Intracellular Sources of Sugars 51 .4 .1

Salvage 5

1 .4 .2

Activation and Interconversion of Monosaccharides 6Glycogen 6Glucose 7Glucuronic acid 8Iduronic acid 8Xylose 8M an nose 8Fucose 9Galactose 1 0N-Acetylglucosamine 1 0N-Acetylgalactosamine 1 0Sialic acids 1 1

1 .5

Sugar Nucleotide Transporters 1 11 .6

Control of Sugar Nucleotide Levels 1 31 .7

Possible Future Directions 1 3References 1 4

2

Nucleotide Sugar Transporters 1 9Rita Gerardy-Schahn and Matthias Eckhard t

2 .1

Introduction 1 92 .2

General Considerations 2 02 .3

The Requirement for Nucleotide Sugar Transporters and Thei rMechanism of Function: A Comprehensive Overview of the Las t20 Years 2 0

2 .4

Molecular Cloning of Nucleotide Sugar Transporters 2 22 .5

The Structure of Nucleotide Sugar Transporters 2 52 .6

The Subcelluar Distribution of Nucleotide Sugar Transporters 2 7

2 .7

Molecular Defects that Cause Inactive UDP-Galactose an dCMP-Sialic Acid Transporters 2 8

2 .8

Association Between Defects in Nucleotide Sugar Transporters an dDiseases 2 9

2 .9

Involvement of Nucleotide Sugar Transporters in the Regulation o fGlycosylation 2 9

2 .10

Future Perspectives 30Acknowledgements 3 1References 3 2

3

Biosynthesis of Oligosaccharyl Dolichol 3 7

Sharon S. Krug3 .1

General Overview 3 7

3 .2

Oligosaccharyl Dolichol 3 8

3 .3

Key Enzymatic Steps in the Assembly Process 3 9

3 .4

Topology of the Assembly Process 4 2

3 .5

Utilization of Oligosaccharyl Dolichol 4 2Acknowledgment 43

References 43

4

Biochemistry and Molecular Biology of the N-Oligosaccharyl-transferase Complex 4 5Roland Knauer and Ludwig Lehle

4 .1

Introduction 454 .2

Biochemistry of OST 464 .2 .1

Lipid-Saccharide Donor 474 .2 .2

Acceptor Specificity of OST 484 .2 .3

Catalytic Mechanism of OST 4 94 .2 .4

Regulation of OST Activity 5 14 .3

Isolation of OST Complexes from Different Sources 5 14 .4

Molecular Biology of OST 5 24 .4 .1

WBP1/OST48 5 44 .4 .2

SWP1/Ribophorin II 5 44 .4 .3

OST1/Ribophorin I 5 54 .4 .4

OST3/OST6 5 54 .4 .5

OST5 5 64 .4 .6

OST4 5 64 .4 .7

OST2/DAD 1 5 74 .4 .8

STT3 5 84 .5

Structural Organization of the OST Complex 5 9Acknowledgments 6 0References 6 0

5

Processing Enzymes Involved in the Deglucosylation of N-LinkedOligosaccharides of Glycoproteins: Glucosidases I and II andEndomannosidase 6 5Robert G. Spiro

5 .1

Introduction 6 55 .2

Glucosidase I 6 65 .3

Glucosidase II 6 85 .4

Endo-a-mannosidase 7 05 .5

Concerted Action of Deglucosylation Enzymes 7 25 .6

Mutants 745 .7

Role of Monoglucosylated N-Linked Oligosaccharides and GlucoseTrimming Enzymes in Regulating Quality Control o fGlycoproteins 7 5

5 .8

Effect of Glucosidase Inhibitors on Viral Proliferation 7 7Acknowledgments 7 8References 7 8

6

u-Mannosidases in Asparagine-linked Oligosaccharide Processin gand Catabolism 8 1Kelley W. Moreme n

6 .1

Overview 8 16 .2

Introduction 82

6.2 .1

Roles of N- and 0-Linked Glycans and Compartmentalization o fBiosynthetic and Catabolic Reactions 8 2

6 .2 .2

Processing of Asn-Linked Oligosaccharides 8 26 .2 .3

Early Trimming Events: importance for quality control glyco -protein degradation and anteriograde transport 8 5

6 .2 .4

Glycoprotein Catabolism : multiple routes for glycoprotei nbreakdown 8 7

6 .2 .5

Consequences of Genetic Defects in Oligosaccharide Biosynthesi sand Catabolism 8 8

6 .3

Mannosidases in Glycoprotein Processing and Catabolism 8 96 .3 .1

Classification of Mannosidases 8 96 .3 .2

Class 1 Mannosidases: enzymes of the ER and Golgi 9 3ER mannosidase I subfamily 9 3Golgi mannosidase I sub-family 9 5Fungal secreted mannosidases 9 7New genes with unknown functions 9 8

6 .3 .3

Class 2 Mannosidases : enzymes of the cytosol, ER, Golgi, andLysosomes 9 8Golgi mannosidase II 99Lysosomal mannosidase 10 1Epididymal/sperm mannosidase 10 3Heterogeneous cluster of mannosidase homologs among eukarya,eubacteria, and archaea 104

6 .4

Conclusions and Future Prospects 106Acknowledgments 107References 107

7

The Role of UDP-Glcyglycoprotein Glucosyltransferase as a Senso rof Glycoprotein Conformations 119Armando J. Parodi

7 .1

Introduction 11 97 .2

General Properties 1207 .3

GT Recognizes Glycoprotein Conformations 12 17 .4

The Primary Structure of the UDP-GlcyglycoproteinGlucosyltransferase 12 2

7 .5

The Role of Monoglucosylated Oligosaccharides in Glycoprotei nFolding 12 3Acknowledgments 12 6References 12 7

8

Mannosyltransferases 12 9Peter Orlean

8 .1

Introduction 12 98 .2

Occurrence of Covalently-linked Mannose 130

8 .2 .1

Eukaryotic Secretory Glycoproteins 13 08 .2 .2

Glycophospholipids 13 08 .2 .3

Eubacterial and Archaeal Mannose-containing Molecules 13 08 .2 .4

C-linked Mannose 13 08 .3

Biochemistry of Mannosyl Transfer 13 18 .3 .1

Many Linkages, Two Donors 13 18 .3 .2

Donor Specificity 13 18 .3 .3

Acceptor Specificity 13 28 .3 .4

Structural Features of Man-T 13 28 .4

Man-T Families and the Pathways They Participate in 13 38 .4 .1

Man-Ts of the ER [1-5] 13 4Alglp 13 4Alg2p/Alg l l p 13 4Dpm lp 13 5Alg3p 13 5Alg9p/PIG-Bp family 13 5Pmtlp family 13 6

8 .4 .2

Golgi Man-Ts and Fungal Mannan Synthesis 13 6Ochlp family 13 7Mnn9p family 13 7Mnn10p/Mnnl lp family 13 8Mnn1p family 13 8Ktrlp family 13 8

8 .4 .3

"Missing " Eukaryotic Man-T 13 88 .4 .4

Eubacterial and Archaeal Man-T 13 98 .5

Coordinating Man Transfer with the Cell Cycle andMorphogenesis 13 9

8 .6

Concluding Remarks 14 0Acknowledgments 140References 14 0

9

Branching of N-Glycans : N-Acetylglucosaminyltransferases 14 5Harry Schachter

9 .1

Introduction 14 59 .2

Processing of N-Glycans within the Endomembrane Assembl yLine 146

9 .3

General Properties of the N-Acetylglucosaminyltransferases 14 89 .3 .1

Domain Structure 14 89 .3 .2

Targeting to the Golgi Apparatus 1509 .4

UDP-GIcNAc :Mana1-3R [GIcNAc to Manal-3] [3-1,2-N-Acetylglucosaminyltransferase I (GnT I, EC 2 .4 .1 .101) 15 0

9 .5

UDP-GIcNAc:Manal-6R [GIcNAc to Mana1-6] ß-1,2-N -Acetylglucosaminyltransferase II (GnT II, E .C. 2 .4 .1 .143) 152

9 .6

The Role of GnT I and II in Mammalian Development 153

9 .7

UDP-GIcNAc:R 1 -Manal-6[GIcNAc(31-2Mana1-3]Manßl-4R 2[GIcNAc to Man(31-4] 13-1,4-N-Acetylglucosaminyltransferase II I(GnT III, E .C. 2 .4 .1 .144) 15 5

9 .7 .1

Overexpression of GnT III Activity 1569 .7 .2

GnT III Activity and Cancer 1579 .8

UDP-GIcNAc:R 1 Manal-3R 2 [G1cNAc to Manal-3 ]Acetylglucosaminyltransferase IV (GnT IV, E .C. 2 .4 .1 .145) 15 7

9 .9

UDP-GlcNAc :R 1 Manal-6R 2 [GIcNAc to Manal-61 (3-1,6-N-Acetylglucosaminyltransferase V (GnT V, E .C .2 .4 .1 .155) 15 8

9 .9 .1

GnT V Activity and Cancer 15 99 .10

UDP-GIcNAc:R 1 (R 2 )Mana1-6R 3 [GIcNAc to Mana1-6 ]13- 1,4-NI-A cetylglucosaminyltran.sferase VI (GnT VI) 16 1

9 .11

GnT VII and GnT VIII 16 1References 16 2

10

The Galactosyltransferases 17 5Nancy L. Shaper, Martin Charron, Neng-Wen Lo, Jane R. Scocca ,and Joel H. Shaper

10 .1

Introduction 17 510 .2

Using the Databanks to Obtain Information on theGalactosyltransferases 177

10 .2 .1

Nomenclature 17710 .3

The Dual Role of (34-Galactosyltransferase-I (ß4GaIT-I) i nOligosaccharide and Lactose Biosynthesis : The Early Days 178

10 .3 .1

ß4GaIT-I : Isolation and Characterization of cDNA Clones 18 110 .3 .2

The Murine 134GaIT-I Gene : Genomic Organization and Structur eof the 5'-End 18 1

10 .3 .3

134GalT-I and Lactose Biosynthesis 18 210 .3 .4

ß4GaIT-I and the Vertebrate ß4GaIT Gene Family 18 210 .3 .5

Evolution of the ß4-Galactosyltransferase Gene Family 18 410 .4

The Vertebrate (33Galactosyltransferase (13GalT) Gene Family 18 510 .4 .1

General Characteristics of the 03-Galactosyltransferase GeneFamily Members 18 6

10 .4 .2

133GaIT-IV : UDP-galactose : GMl (13-galactosyltransferase (GM 1Synthase ; Ga1T-3) 18 7

10 .4 .3

Other Vertebrate (3-Galactosyltransferase Activities 18 710 .4 .4

UDP-Galactose:Ceramide 13-Galactosyltransferase (CGaIT ; EC2 .4 .1 .45) 18 7

10 .5

The Vertebrate a3-Galactosyltransferase Gene Family 18 8

10 .5 .1

a3-Galactosyltransferase (a3GalT : UDP-Gal :Gal[34GlcNAca3 -Galactosyltransferase ; EC 2.4 .1 .87) 18 8

10 .5 .2

The Blood Group B a3-Galactosyltransferase (EC 2 .4 .1 .37) 190

10 .5 .3

The Forssman Glycolipid Synthetase (EC 2 .4 .1 .88) 19 1

10 .5 .4

Evolution of the a3GalT Gene Family 191

10 .6

A UDP-Ga1:Galß3GalNAc a4Galactosyltransferase Activity 192Acknowledgments 192References 19 2

11

Fucosyltransferases 19 7Ernesto T A. Marques, Jr.

11 .1

Introduction 19 711 .2

General Characteristics 19 811 .2 .1

Nomenclature 19 811 .2 .2

Gene Structure 19 911 .2 .3

Sequence Peptide Motifs 19 911 .2 .4

Specificity 19 911 .2 .5

Protein Structure and Topology 20 011 .2 .6

Enzymatic Reaction Mechanism 20 111 .2 .7

Inhibitors 20 311 .3

Specific Fucosyltransferases 20 311 .3 .1

GDP-Fucose : Fuca l (Fucal,2Fuc)a2-fucosyltransferase 20 411 .3 .2

GDP-Fucose : Gal (31 (Fucal ,2Gal)a2-fucosyltransferase 20411 .3 .3

GDP-Fucose : Galß1,4/3G1cNAc(Fucal,3/4G1cNAc)a3/4 -fucosyltransferases 204Blood group Lewis : FucT III, V and VI 204Myeloid enzyme: FucT IV 205Leukocyte enzyme: FucT VII 206Neuronal enzyme: FucT IX 206

11 .3 .4

GDP-Fucose : Galß1,3GlcNAc(Fuca1,3G1cNAc) bacterial(Helicobacter pylori) a3-fucosyltransferase 207

11 .3 .5

GDP-Fucose: GIcNAc-N(Fucal,6GlcNAc)a6fucosyltransferases 20711 .3 .6

GDP-Fucose: O-Ser(Fucal-O-Ser)GIcNAc polypeptidefucosyltransferases 207

11 .3 .7

Unconventional Types of Fucosylation: Fucßl-P-Ser and cyto -plasmic Fucal,2-Galß1,3-GIcNAc-Pro (Dictyostelium discoideum) 207Fucß l -P-Ser 207Fucal,2-Ga1ß1,3-GIcNAc-Pro 208Acknowledgments 208References 208

12

Sialyltransferases 21 3Joseph T. Y. Lau and Sherry A . Wuensch

12 .1

Introduction 21 312 .2

General Features of Sialyltransferases 21 312 .3

Cloning and Identification Strategies for Sialyltransferases 21 512 .4

Sialyltransferase Classification and Nomenclature 21 612 .5

The a2,3-ST Family 21 612 .6

The a2,6-ST Family 21 712 .7

The a2,8-ST Family 218

12 .8

Regulation and Functionality of Sialyltransferases 21 9References 22 1

13

Biochemistry of Sialic Acid Diversity 22 7Roland Schaue r

13 .1

Introduction 22 713 .2

Occurrence and Biosynthesis 22 713 .3

General Biological Functions 22913 .4

N-Glycolylneuraminic Acid 23 113 .5

O-Acetylated Sialic Acids 23413 .6

0-Methylated and 0-Sulfated Sialic Acids 23 8Acknowledgments 239References 23 9

14

Carbohydrate Sulfotransferases 24 5Steven D. Rosen, Annette Bistrup, and Stefan Hemmerich

14 .1

Introduction 24 514 .2

Basic Features of Sulfotransferase Reactions 24 514 .3

Tyrosine Sulfation 24 614 .4

Diversity of Carbohydrate Sulfation 24 614 .5

Biochemical Demonstration of Carbohydrate Sulfotransferases 24 914 .6

Molecular Cloning of Carbohydrate Sulfotransferases 25 014 .7

Primary Structures of Carbohydrate Sulfotransferases 25 2Acknowledgments 25 6References 25 6

15

Novel Variant Pathways in Complex-type Oligosaccharid eSynthesis 26 1Dirk H. van den Eijnden

15 .1

Introduction 26 115 .2

The lacNAc Pathway of Complex-type Oligosaccharide Synthesis 26 115 .3

Occurrence and Biology of lacdiNAc-based Complex-typ eOligosaccharides 26 2

15 .4

Biosynthesis of lacdiNAc Backbone Units 26 315 .5

The lacdiNAc Pathway of Complex-type OligosaccharideSynthesis 26 4

15 .6

Other Shared Properties of ß4-GaIT and ß4-GaINAcT 26 615 .7

Cloning of a snail UDP-GlcNAc :G1cNAcß-R ß4-N-acetylglucosaminyltransferase 26 6

15 .8

The Chitobio Pathway of Complex-type Oligosaccharid eSynthesis 26 7

15 .9

Competition Between Pathways 26 715 .10

Concluding Remarks 26 9References 269

16

Control of Mucin-Type O-Glycosylation : O-Glycan Occupancy isDirected by Substrate Specificities of Polypeptide GaINAc -Transferases 27 3Helle Hassan, Eric P. Bennett, Ulla Mandel, Michael A .Hollingsworth, and Henrik Clausen

16 .1

Introduction 27 316 .2

The Mammalian UDP-GaINAc : Polypeptide Ga1NAc-TransferaseGene Family 274

16 .3

The Ga1NAc-Transferase Gene Family is Evolutionarily Old 27616 .4

The Kinetic Properties of Ga1NAc-Transferase Isoforms ar eDifferent 278

16 .4 .1

Lessons from in vivo Analysis of Ga1NAc-transferase Substrat eSpecificities 27 9

16 .4 .2

Lessons from in vitro Analysis of the Acceptor SubstrateSpecificities of Ga1NAc-transferase Isoforms 280Isoforms may have distinct acceptor substrate specificities 28 1Isoforms may have overlapping substrate specificities 28 3Isoforms may act in different order on substrates with multipleacceptor sites 28 3Isoforms may require prior (Ga1NAc) glycosylation 28 3

16 .5

Expression of the Ga1NAc-Transferase Genes are Differentiall yRegulated 28 5

16 .6

Predictive Value of in vitro 0-glycosylation? 28 816 .7

Conclusions and Future Perspectives 28 8References 28 9

17

Glycosyltransferase Inhibitors 29 3Xiangping Qian and Monica M. Palcic

17 .1

Introduction 29 317 .2

Inhibitors of Glycosyltransferases 29617 .2 .1

Inhibitors of Galactosyltransferases 296Inhibitors of (31,4-galactosyltransferase 296Inhibitors of al,3-galactosyltransferase 29 7

17 .2 .2

Inhibitors of Fucosyltransferases 298Inhibitors of a1,2-fucosyltransferases 300Inhibitors of a 1,3-fucosyltransferases 300

17 .2 .3

Inhibitors of Sialyltransferases 30 1Inhibitors of a2,6-sialyltransferase 302Inhibitors of a2,3-sialyltransferase 304

17 .2 .4

Inhibitors of N-Acetylglucosaminyltransferases 30517 .2 .5

Inhibitors of Human Blood Group A and B Glycosyltransferases 30617 .3

Summary 309Acknowledgments 309References 309

18

Biosynthesis of the O-Glycan Chains of Mucins and Mucin Typ eGlycoproteins 31 3Inka Brockhause n

18 .1

Summary 31 318 .2

Introduction 31 318 .3

Structures of O-Glycans 31 418 .4

Functions of Mucin Type O-Glycans 31 418 .5

Primary O-Glycosylation 31 518 .6

Synthesis of O-Glycan Core 1 31 518 .7

Synthesis of O-Glycan Core 2 31 718 .8

Synthesis of O-Glycan Core 3 31 918 .9

Synthesis of O-Glycan Core 4 31 918 .10

Synthesis of O-Glycan Cores 5-8 31 918 .11

Elongation and Branching Reactions 32 018 .12

Synthesis of Terminal Structures 32 1Acknowledgments 324References 32 4

19

Glycosyltransferases in Glycosphingolipid Biosynthesis 329Subhash Basu, Kama/ Dos, and Manju Basu

19 .1

Introduction 32919 .2

Fucosyltransferases in Glycolipid Biosynthesis 32919 .3

Galactosyltransferases in Glycolipid Biosynthesis 33 219 .4

N-Acetylgalactosaminyltransferases in Glycolipid Biosynthesis 33419 .5

N-Acetylglucosaminyltransferases in Glycolipid Biosynthesis 33619 .6

Sialyltransferases in Glycolipid Biosynthesis 33 719 .7

Glucuronyltransferases in Glycolipid Biosynthesis 340Acknowledgments 342References 342

20

Biosynthesis of Glycogen 349Peter J. Roach

20 .1

Summary 349

20 .2

Introduction 35020 .3

Glycogenin and the Initiation of Glycogen Synthesis 35 1

20 .3 .1

History 35 1

20 .3 .2

Properties 35 120 .3 .3

Reaction Mechanism 35 2

20 .3 .4

Domain Structure 35 2

20 .3 .5

Function 35 4

20 .4

Glycogen Synthase and the Bulk Synthesis of Glycogen 35 4

20 .4 .1

Properties 354

20 .4 .2

Structure of Glycogen Synthase 35 5

20 .4 .3

Branching Enzyme 35 6

20 .5

Intermediates in the Biosynthesis of Glycogen 357

20 .6

Conclusion 35 8Acknowledgments 35 9References 35 9

21

Biosynthesis of Hyaluronan 36 3Paraskevi Heldin and Torvard C. Laurent

21 .1

Introduction 36 321 .2

Site of Biosynthesis 3 6421 .3

Biosynthetic Precursors 36421 .4

Hyaluronan Synthases 36 521 .4 .1

Microbial Enzymes 36 521 .4 .2

Vertebrate Synthases 36621 .5

Mechanism of Synthesis 36 721 .5 .1

Chain Elongation 36 821 .5 .2

Translocation 36921 .5 .3

Shedding 36921 .6

Regulation of HA Synthesis 37021 .7

Concluding Remarks 37 1Acknowledgments 372References 37 2

22

Biosynthesis of Chondroitin Sulfate and Dermatan SulfateProteoglycans 37 5Geetha Sugumaran and Barbara M. Vertel

22 .1

Introduction 37 522 .2

Proteoglycan Structure 37 922 .2 .1

Proteoglycans and Their Core Proteins 37 922 .2 .2

What Initiates GAG Chain Addition? 38 122 .2 .3

The Linkage Region 38 122 .2 .4

CS and DS Chains 38 222 .3

Biosynthesis of CS and DS Proteoglycans 38 322 .3 .1

Biosynthesis of the Core Protein 38 322 .3 .2

Origin of Sugar and Sulfate Precursors 38422 .3 .3

Addition of the Linkage Oligosaccharides 38 5Xylosylation 38 5Galactosylation 386Addition of GIcA and completion of the common tetrasaccharidelinkage region 38 7Initiation of CS/DS chains by addition of the first GaINAc 38 8

22 .3 .4

Formation of the CS/DS Chains 38 8Addition of the repeating disaccharides 388Epimerization of GIcA to IdoA to form DS 389Sulfation of GaINAc 3 90Sulfation of uronic acid 391

22 .4

Concluding Remarks/Perspectives 39 1Acknowledgments 392References 392

23

Biosynthesis of Heparin and Heparan Sulfate Proteoglycans 39 5Lena Kjellen and Ulf Lindah l

23 .1

Introduction 39 523 .2

The Proteoglycans : Structure, Location and Functions 39 623 .3

Biosynthesis of the Polysaccharide Backbone 39 623 .4

Outline of Polymer-Modification Reactions 39 723 .4 .1

The N-Deacetylase/N-Sulfotransferases 39 923 .4 .2

The C5-Epimerase 39 923 .4 .3

The 2-0-Sulfotransferase 39 923 .4 .4

The 6-0-Sulfotransferases 40 023 .4 .5

The 3-0 Sulfotransferases 40 023 .5

The Products, Heparin and Heparan Sulfate 40023 .6

Interactions with Proteins 40 123 .7

Regulation of HS Biosynthesis 40 2References 40 3

24

Biosynthesis of Proteoglycans with Keratan Sulfates 40 7James L. Funderburgh

24 .1

Introduction : Keratan Sulfate Renaissance 40 724 .2

Keratan Sulfate Structure and Distribution 40 724 .2 .1

Corneal KS 40 824 .2 .2

Non-corneal KSI 40 924 .2 .3

KSII 40 924 .2 .4

KSIII 41 024 .3

Keratan Sulfate Proteoglycans 41 024 .3 .1

S LRPs 41 024 .3 .2

Aggrecan 41 124 .3 .3

Cell-Associated KS 41 124 .3 .4

Brain 41 224 .4

Enzymatic Reactions of KS Biosynthesis 41 224 .5

Metabolic Control of KS Synthesis 41 3Acknowledgments 41 4References 41 4

25

The Biosynthesis of GPI Anchors 41 7Yasu S. Morita, Alvaro Acosta-Serrano, and Paul T. Englund

25 .1

Introduction 41 725 .2

Structure of GPI Anchors 41 725 .2 .1

Glycan Core Modifications 417

25 .2 .2

Variations in Anchor Lipid Structure 41 925 .3

GPI Precursor Synthesis 41 925 .3 .1

G1cNAc-PI Synthesis 42025 .3 .2

G1cNAc-PI Deacetylation 42 125 .3 .3

Inositol Acylation 42 125 .3 .4

GPI Mannosylation 42225 .3 .5

Transfer of EtN-P 42 325 .3 .6

Lipid Remodeling 42 325 .3 .7

Addition of Carbohydrate Side Chains 42425 .3 .8

Topology of Biosynthetic Pathways 42425 .4

Attachment of the GPI Precursor to a Protein 42 525 .4 .1

Basic Features 42 525 .4,2

Protein Machinery for GPI Addition 42625 .4 .3

Signal Sequence for GPI Addition 42625 .5

Evolution of GPI Biosynthesis 42625 .6

Future Studies 42 7Acknowledgments 427References 42 7

26

Escherichia call Lipid A : A Potent Activator of Innate Immunity 43 5Teresa A . Garrett and Christian R . H. Raet:

26 .1

Introduction 43 526 .2

Structure of Lipopolysaccharide 43 526 .3

Lipid A Biosynthesis in E. call 43 726 .3 .1

Acylation of UDP-G1cNAc 43 926 .3 .2

Disaccharide Formation 44026 .3 .3

Phosphorylation by the Lipid A 4' Kinase 44026 .3 .4

Kdo Addition and the Late Acyltransferases 44 126 .3 .5

Other Acyltransferases 44226 .3 .6

Transport of Lipid A and the Role of MsbA 44226 .4

Lipid A Activation of Signal Transduction in Animal Cells 44426 .5

Summary 44 7Acknowledgments 447References 447

II

Glycosidases 45 3

27

Lysosomal Degradation of Glycolipids 45 5Thomas Koller and Konrad Sandhoff

27 .1

Summary 45 527 .2

Introduction 45 527 .3

Mechanisms of Lysosomal Glycolipid Degradation 45 627 .3 .1

Glycosidases 456

27 .3 .2

Topology of Endocytosis and Lysosomal Glycolipid Degradation 45 727 .3 .3

Sphingolipid Activator Proteins 45 8The GM2-activator and its role in lysosomal digestion 459SAP-A to SAP-D 460

27 .3 .4

Lateral Pressure 46027 .3 .5

Lipid Composition 46 127 .3 .6

Membrane Curvature 46227 .4

Degradation of Selected Lipids 46227 .4 .1

Ganglioside GM2 46227 .4 .2

Lactosylceramide 46427 .4 .3

Glucosylceramide 46427 .4 .4

Ceramide 46 527 .4 .5

Sphingomyelin 46 527 .4 .6

Sulfatide 46 527 .4 .7

Galactosylceramide 46627 .5

Pathobiochemistry 46627 .5 .1

Animal Models for Sphingolipidoses 46727 .5 .2

Therapy 46927 .6

Future Directions 470References 470

28

Lysosomal Degradation of Glycoproteins 473Nathan N. Aronson, Jr.

28 .1

Summary 47328 .2

Introduction 47328 .3

Roles of Lysosomes 474

28 .4

Lysosomal Degradation of N-Linked Glycoproteins 47528 .4.1

General Features 47528 .4.2

Carbohydrate Digestion 47 628 .4.3

Protein and Linkage Hydrolysis 476

28 .5

Formation of Thyroid Hormone via Lysosomal Degradation ofThyroglobulin 47 7

28 .5 .1

Synthesis of Thyroid Hormone 47 7

28 .5 .2

Carbohydrate Degradation 47 8

28 .5 .3

Proteolysis 47 9

28 .6

Degradation of Free Polymannose-Type Oligosaccharides Derive dfrom N-Linked Glycoproteins During Biosynthesis 47 9

References 48 1

29

Sialidases 48 5

Garry Taylor, Susan Crennell, Carl Thompson, and Marin a

Chuenkova29 .1

Abstract 48 5

29 .2

Introduction 485

29 .3

Influenza Virus Neuraminidase 48 629 .4

Paramyxovirus Hemagglutinin-Neuraminidase (HN) 48 729 .5

Non-Viral Sialidases 48 729 .6

Small Sialidases 49 029 .7

Large Sialidases 49 129 .8

T . cruzi Trans-Sialidase (TS) 49 129 .9

Conclusion 49 3Acknowledgments 49 4References 494

30

Microbial Glycosidases 49 7Kenji Yamamoto, Su-Chen Li, and Yu-Teh L i

30 .1

Exo-Glycosidases 49 730 .1 .1

a-Glucosidase 49 730 .1 .2

ß-Glucosidase 49 830 .1 .3

a-Galactosidase 49 830 .1 .4

ß-Galactosidase 49 930 .1 .5

a-Mannosidase 50 030 .1 .6

ß-M annosidase 50 030 .1 .7

ß-N-Acetylhexosaminidase 50 130 .1 .8

a-N-Acetylgalactosaminidase 50 130 .1 .9

a-L-Fucosidase 50 230 .1 .10

13-D-Fucosidase 50 330 .1 .11

Sialidase 50 330 .1 .12

KDNase 50430 .1 .13

a-L-Rhamnosidase 50430 .1 .14

ß-Xylosidase 50 530 .2

Endo-Glycosidases 50 530 .2 .1

Endo-ß-N-acetylglucosaminidase 50 530 .2 .2

Peptide-N-glycanase F 50 630 .2 .3

Endo-a-N-acetylgalactosaminidase 50 630 .2 .4

Endo-ß-galactosidase 50 730 .2 .5

Endoglycoceramidase 50 7References 50 8

31

Glycoprotein Processing Inhibitors 51 3Magid Osser and Alan D. Elbein

31 .1

Introduction 51 331 .2

Structural Classification 51 531 .3

Distribution of Glycosidase Inhibitors in the Plant Kingdom 51 531 .4

Isolation and Structural Determination 51 631 .5

Glycosidase Inhibitory Activity 51 731 .6

Structure-Activity Relationships 51 831 .7

N-Linked Oligosaccharide Processing 51 931 .8

Inhibitors of N-Linked Oligosaccharide Processing 522

31,8 .1

Glucosidase Inhibitors 52 231 .8 .2

Mannosidase Inhibitors 52 531 .9

Summary and Future Prospects 52 8References 52 9

Index I 1