Table Of ContentMEDICAL
INTELLIGEN CE
UNIT
GLYCOPROTEINS
AND HUMAN DISEASE
Inka Brockhausen, Ph.D.
William Kuhns, M.S., M.D.
Department of Biochemistry
Research Institute
Hospital for Siek Children
University ofToronto
Toronto, Ontario, Canada
Springer-Verlag
Berlin Heidelberg GmbH RG. lANDES CoMPANY
AuSTIN
MEDICAL INTELUGENCE UNIT
GLYCOPROTEINS AND HUMAN DISEASE
R.G. LANDES COMPANY
Austin, Texas, U.S.A.
International Copyright © 1997 Springer-Verlag Berlin Heidelberg
Originally published by Springer-Verlag in 1997
Softcover reprint of the hardcover 1st edition 1997
All rights reserved.
No part of this book may be reproduced or transmitred in any form or by any means, elec
tronic or mechanical, including photocopy, recording, or any information srorage and retrieval
system, wichout permission in writing from the publisher.
~Springer
ISBN 978-3-662-21962-1
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and usage of equipment and devices, as sec fonh in this book, are in accord with current recommend
ations and practice at the time of publication, they make no warranty, expressed or implied, wich
respect to material described in this book. In view of the ongoing research, equipment development,
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herein.
Library of Congress Cataloging-in-Publication Data
Brockhausen, Inka, 1944-
Glycoproteins and human disease I Inka Brockhausen, William Kuhns.
p. cm. - (Medical intelligence unit)
Includes bibliographical references and index.
ISBN 978-3-662-21962-1 ISBN 978-3-662-21960-7 (eBook)
DOI 10.1007/978-3-662-21960-7
1. Glycoproteins-Metabolism-Disorders. I. Kuhns, Williarn, M.D.
li. Tide. III. Series.
[DNLM: 1. Glycoproteins. 2. Disease QU 55 B863g 1996}
RC632.G57B76 1996
616.3'995-dc20
DNLM/DLC 96-43740
for Library of Congress CIP
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AB BR E VIAT I0 NS
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AFP alpha fero-protein
AIDS acquired immunodeficiency syndrome
ALL acute lymphocytic leukemia
AML acute myeloid leukemia
ßAPP ß-amyloid precursor protein
BHK cells baby hamster kidney cells
CAM cell adhesion molecule
CDGS carbohydrate deficient glycoprotein syndrome
CEA carcino-embryonic antigen
CF cystic fibrosis
CFTR cystic fibrosis transmembrane conductance regulator
CHO cells Chinese hamster ovary cells
CLL chronic lymphocytic leukemia
CML chronic myelogenous leukemia
CRD carbohydrate recognition domain
CSF colony stimulating factor
Dol-P dolichol-phosphate
Dol-PP dolichol-pyrophosphate
DTT dithiothreitol
EBV Epstein-Barr virus
EC endothelial cells
ECM extracellular matrix
EGF epidermal growth factor
ELISA enzyme linked immunosorbent assay
EPO erythropoietin
ER endoplasmic reticulum
FSH follicle stimulating hormone
Fuc fucose
Gal galactose
GalNAc N -acetylgalactosamine
G-CSF granulocyte colony stimulating factor
Glc glucose
GlcNAc N -acetylglucosamine
GM-CSF granulocyte macrophage colony stimulating factor
GP glycoprotein
GPI glycosylphosphatidylinositol
GVHD graft versus hast disease
HBV hepatitis B virus
hCG human chorionic gonadotropin
HEMPAS hereditary erythroblastic multinuclearity with
acidified serum Iysis test
HIV human immunodeficiency virus
HPLC high performance liquid chromatography
HPAEC high pressure anion exchange chromatography
HSV
Herpes Simplex virus
HUVEC human umbilical cord vein endothelial cells
IGF insulin-like growth factor
LAD leukocyte adhesion deficiency
lamp lysosomal associated membrane protein
LH luteinizing hormone
Man mannose
Man-6-P mannose-6-phosphate
MHC major histocompatibility complex
NCAM neural cell adhesion molecule
Neu5Ac 5-N-acetylneuraminic acid
Neu5Gc 5-N -glycolylneuraminic acid
NK natural killer
NMR nuclear magnetic resonance
OA osteoarthri tis
PAPS 3-phospho-adenosine-5 '-phosphosulphate
PGM phosphoglucomutase
PHA phytohemagglutinin
PMN polymorphonuclear leukocytes
PSA polysialic acid
SA sialic acid
TNF tumor necrosis facror
tPA tissue plasminogen activator
TRH thyrotropin-releasing hormone
TSH thyroid stimulating hormone
UEA Ulex europaeus agglutinin
uv ultraviolet light
vWF von Willebrand factor
WAS Wiscott-Aldrich syndrome
WGA wheat germ agglutinin
Xyl xylose
CO NTENTS
r;::::=========== =========:=::::;']
1. Abstract ...................................................................................... 1
2. lntroduction ............................................•.................................. 3
3. Structures of a-N-Acetylgalactosamine-Ser/Thr-Linked
Oligosaccharides (0-glycans) ...................................................... 5
3.A. Structural Analysis ......................................................................... 5
3.B. Common 0-Glycan Core Structures ............................................. 6
3.C. Complex 0-Glycan Structures ...................................................... 7
4. Biosynthesis ofO-Glycans ........................................................ 13
4.A. Nucleotide Sugar Transport ........................................................ 15
4.B. Initiation ofO-Glycan Synthesis ................................................. 16
4.C. Synthesis ofO-Glycan Cores ....................................................... 16
4.0. Elongation Reactions .................................................................. 20
4.E. Terminal Reactions ...................................................................... 21
4.F. Addition ofTerminal Blood Group Antigens .............................. 24
4.G. Biosynthesis of Sulfated 0-Glycans ............................................. 24
5. Structures ofß-N-Acetylglucosamine-Asn-Linked
Oligosaccharides (N-Glycans) ................................................... 33
6. Biosynthesis ofN-Glycans ........................................................ 37
6.A. Biosynthetic Reactions in the Endoplasmic Reticulum ................ 37
6.B. Golgi Processing Reactions .......................................................... 38
7. Less Common 0-Linked Carbohydrates of Glycoproteins ........ 49
7.A. 0-GlcNAc ................................................................................... 49
7.B. 0-Man ........................................................................................ 49
7.C. 0-Fuc and 0-Glc ........................................................................ 50
8. Control Mechanisms in the Biosynthesis
ofN- and 0-Glycans ....................................•........................... 53
8.A. Genetic Control of Glycosyltransferases ....................................... 53
8.B. Intracellular Localization ofProcessing Enzymes ......................... 54
8.C. Factors Affecting Enzyme Activities ............................................. 55
8.0. Glycosyltransferase Substrate Specificities ................................... 55
8.E. Factors Affecting the Availability of Substrates ............................. 57
9. Glycoproteins and Cell Adhesion Functions ............................. 63
9 .A. Ce! I Adhesion Molecules ............................................................. 64
9.B. Mammalian Leetins ..................................................................... 65
9.C. Selectins ...................................................................................... 68
9. 0. Extracell ular Matrix and Integrins ............................................... 70
9.E. Fertilization ................................................................................. 71
10. Role of Glycoproteins of the Immune
and Blood Coagulation Systems ............................................... 79
10.A. Immune System ........................................................................ 79
1O .B. Blood Groups ............................................................................ 81
10.C. Blood Thrombus Formation and Dissolution ............................ 82
11. Growth and Hormone-Related Functions of Glycoproteins
and Cell Surface Receptors ....................................................... 89
1l.A. Growth, Differentiation and Development ................................ 89
11.B. Apoptosis ................................................................................... 93
1l.C. Hormonesand Cyrokines .......................................................... 93
1l.D. Cell Surface Receptor Functions ............................................... 96
12. General Glycoprotein Functions ............................................. 103
12.A. Role ofMucins ........................................................................ 103
12.B. Functions of Sulfated Oligosaccharides .................................... 104
12.C. Ion Channels ........................................................................... 105
12.D. Chaperones ............................................................................. 106
12.E. Enzymes .................................................................................. 106
13. Glycosylation in Leukemia and Blood Related Disorders ........ 113
13.A. Leukemia ................................................................................. 113
13.B. Blood-Related and Vascular Diseases ....................................... 119
14. Glycosylation in Cystic Fibrosis .............................................. 125
14.A. CFTR ...................................................................................... 125
14.B. Oligosaccharide Structures of Cystic Fibrosis Mucins .............. 126
14.C. Biosynthesis ofMucins in Cystic Fibrosis Cells ....................... 127
14.D. Bacterial Infections in Cystic Fibrosis Patients ........................ 127
14.E. Animal Models for Studies of Cystic Fibrosis ........................... 127
15. Inflarnmatory Diseases ............................................................ 131
15.A. RheumatoidArthritis ............................................................... 132
15.B. lnflammatory Disease in the lntestines .................................... 132
15.C. lnflammation of the Liver ....................................................... 133
16. Carbohydrate Deficiency Diseases .......................................... 137
16.A. Leukocyte Adhesion Deficiency ............................................... 137
16.B. HEMPAS ................................................................................ 138
16.C. Carbohydrate Deficient Glycoprotein Syndrome .................... 138
17. Microorganisms-...................................................................... 145
17 .A. Bacterial lnfections .................................................................. 14 5
17.B. Viral lnfections ........................................................................ 146
17.C. AIDS ....................................................................................... 147
17.D. Parasitic Infections .................................................................. 149
