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COMPREHENSIVE
GLYCOSCIENCE
SECOND EDITION
VOLUME 1
This page intentionally left blank
COMPREHENSIVE
GLYCOSCIENCE
SECOND EDITION
EDITOR IN CHIEF AND VOLUME EDITOR
JOSEPH J. BARCHI JR.

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute,
Frederick, Maryland, United States
VOLUME 1
INTRODUCTION TO GLYCOSCIENCE, GLYCAN STRUCTURE AND FUNCTION

Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
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No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including
photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how
to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the
Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted
herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in
research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods,
compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the
safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or
damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
ISBN 978-0-12-819475-1
For information on all publications visit our

website at http://store.elsevier.com
Publisher: Oliver Walter

Acquisitions Editor: Blerina Osmanaj
Content Project Manager: Michael Nicholls
Associate Content Project Manager: Fahmida Sultana
Designer: Greg Harris
FRONT COVER IMAGES: (Upper Left) Cartoon of a positively charged glycopolymer-coated nanoparticle (thanks to Diana Diaz-Dussan
for help with this image). (Lower Left) 3D structure (PDB 4N3C) of a truncated form of O-GlcNAc transferase (OCT4.5 derived from
Chapter 3.06 by Jiang). (Upper Right) Conformational free energy landscape of pyranosyl oxocarbenium ions, depicting global and local
minima; from Chapter 2.03 by Codée. (Lower Right) Logos from various glycan informatic websites that have been curated or expanded
since the first edition. The figure shows them radiating from Earth, indicating the multi-national aspect of the sites that now connect
scientists of all disciplines from around the globe. (Center) Structure of the SARS-CoV-2 spike protein ectodomain derived from extended
molecular dynamics simulations, including purported glycans from all included glycosylation sites. The snapshot is an overhead view of
the protein with the viral membrane as the background; the lipids in the bilayer are rendered in gray van der Waals spheres; the editors
thanks Elisa Fadda, National University of Ireland, Maynooth, for this figure.
EDITOR BIOGRAPHIES
Editor-in-Chief
Joe Barchi received his PhD in synthetic/marine natural products chemistry from
the University of Hawaii and was a postdoctoral fellow at Duke University.
He then joined the National Cancer Institute as a staff fellow in the Laboratory
of Medicinal Chemistry in 1988 where he rose to his current position of senior
scientist/principal investigator and NMR facility head at the newly formed Chem-
ical Biology Laboratory. His main research interests are in synthetic medicinal
chemistry as it relates to carbohydrate-based drug design, the development of
novel sugar-conjugated nanoparticles, and the high-resolution structural analysis
of sugars, glycopeptides, and small molecule drug candidates by NMR spectros-
copy. Dr Barchi’s career at the NCI has spanned a wide breadth of drug discovery
efforts, including the synthesis of PKC and reverse transcriptase inhibitors, the
development of glycopeptide antigens as vaccine candidates against HIV and
cancer, as well as the discovery of several glycopeptide analogues of antiprolifera-
tive factor (APF), a negative growth factor isolated from patients with interstitial
cystitis. Current focus in the lab is the discovery of novel nanoplatforms for the delivery and therapeutic
applications of immunogenic glycopeptides, the search for selective antitumor agents based on APF, and the
conformational analysis of these synthetic analogues by NMR spectroscopy to guide further discovery efforts. He is
on the editorial board of PlosOne, Current Cancer Drug Targets (Bentham Science Publishers) and Carbohydra-
teResearch (Elsevier). He has edited books and journal issues on topics such as Glyconanotechnology and Drug
Discovery.
Volume Editors
Ravin Narain, PhD, P.Eng., FRSC is a professor in the Department of Chemical

and Materials Engineering, University of Alberta, Canada. Prof. Narain has
made significant contributions to research on the design, fabrication, and
characterization of novel carbohydrate-based materials (glycopolymers, hydro-
gels, and nanomaterials) for a wide range of applications. His research has
also covered biomaterials, nanomedicine, and regenerative medicine, with
an emphasis on developing advanced materials as cancer therapeutics, anti-
fouling and antimicrobial uses, and cell/tissue engineering advances. He has
published over 180 articles and has edited several books namely Engineered
Carbohydrate-Based Materials for Biomedical Applications (Wiley), Chemistry of
Bioconjugates (Wiley), Glycopolymers: Synthesis and Applications (Smithers &
Rapra), and Polymers and Nanomaterials for Gene Therapy (Woodhead Publish-
ing & Elsevier). He is also on the Editorial Board for Polymer Chemistry (RSC),
Biomacromolecules (ACS) and Polymers (MDPI). He was the recipient for a
Distinguished Visiting Scientist Award from CSIRO (Manufacturing),
Melbourne, Australia (2017–18).
v
vi Editor Biographies
Naoyuki Taniguchi graduated from the Faculty of Medicine, Hokkaido Univer-

sity, and obtained his MD in 1967 and then PhD in 1972 from the same
university. He became assistant professor of the Department of Preventive
Medicine, Hokkaido University, and visiting associate professor at the Depart-
ment of Biochemistry, Connell University Medical School, New York. In 1977 he
became associate professor at Cancer Institute, Hokkaido University Faculty of
Medicine. In 1986, he became professor and chair of the Department of Bio-
chemistry at the Osaka University Medical School. In 2006, after retirement he
became Professor Emeritus, Osaka University, and an endowed chair professor
of Osaka University. Meanwhile, he launched the Systems Glycobiology
Research Group at RIKEN in 2007 and served as the group director until 2018.
Then he was recruited to the head of Department of Glyco-Oncology, Research
Center of Osaka International Cancer Institute. Since 2019 he served as the
director of the Research Center. His research interest is mainly focused on the
functional and structural changes of glycans in relation to various diseases including cancer. He has received
several distinguished awards, such as IGO (International Glycoconjugate Organization) Award in 2001, Medal
with Purple Ribbon from the Emperor of Japan in 2005, HUPO (Human Proteome Organization) Distin-
guished Service Award in 2009, and Japan Academy Prize in 2011. He also served as president in the 75th
Annual Meeting of the Japanese Biochemical Society in 2005 and as secretary general in the 20th IUBMB
11FAOBMB Congress in 2006 and the President of the Society for Glycobiology in 2014.
Sébastien Vidal received his PhD in organic chemistry in 2000 (University of

Montpellier, France – Prof. Jean-Louis Montero and Prof. Alain Morère) on the
synthesis of mannose 6-phosphate analogues. He then moved to UCLA with Sir
J. Fraser Stoddart to study glycodendrimers. In 2003, he joined NREL (Golden,
Colorado) with Prof. Joseph Bozell and studied the combination of organome-
tallic and carbohydrate chemistries. He obtained a CNRS position at University
of Lyon in 2004 and started his independent career on carbohydrate chemistry
and applications in biology. In 2019, he has joined the Department of Chemical
Biology at the Institut de Chimie des Substances Naturelles (Université Paris-
Saclay). Sébastien Vidal’s research interests are primarily on carbohydrate-lectin
interactions through the design of multivalent glycoclusters and their applica-
tion in anti-infectious therapeutic strategies. Another aspect is dealing with the
design of synthetic methodologies to construct bio-active glycoconjugates from
(C-)glycosylation to protecting group strategies and conjugation techniques
(e.g. azide-alkyne cycloaddition).
Spencer Williams was born and raised in Albany, Western Australia.

He graduated from the University of Western Australia with a B.Sc. (Hons.)
(1994) and studied for his PhD (1998) in carbohydrate chemistry at the same
institution with Prof. Robert (Bob) Stick. He received postdoctoral training in
the laboratories of Prof. Stephen Withers at the University of British Columbia
and Prof. Carolyn Bertozzi at the University of California at Berkeley, where he
gained a solid grounding in enzyme mechanism and glycobiology. He was
appointed in 2002 at the University of Melbourne, where he is now professor
of chemistry. His interests include carbohydrate chemistry and biochemistry,
pathways of carbohydrate metabolism, medicinal chemistry, enzyme mecha-
nism, and glycoimmunology.
LIST OF CONTRIBUTORS FOR VOLUME 1
Marya Ahmed Robert S Haltiwanger

Department of Chemistry; Faculty of Sustainable Design Department of Biochemistry and Molecular Biology,
Engineering, University of Prince Edward Island, Complex Carbohydrate Research Center, University of
Charlottetown, PE, Canada Georgia, Athens, GA, United States
Kiyoko F Aoki-Kinoshita Mark R Hardy
Glycan & Life Systems Integration Center (GaLSIC) and Mark R. Hardy Consulting LLC, Meriden, NH, United
Faculty of Science and Engineering, Soka University, States
Tokyo, Japan
Lisa A Holland
Joseph J Barchi Jr Department of Chemistry, West Virginia University,
Head, Glycoconjugate and NMR Section, Chemical Biology Morgantown, WV, United States
Laboratory, Center for Cancer Research, Frederick, MD,
Hsu Chen Hsu
United States
Institute of Atomic and Molecular Sciences, Academia
C Eugene Bennett Sinica, Taipei, Taiwan
Department of Chemistry, West Virginia University,
Shih-Pei Huang
Morgantown, WV, United States
Institute of Atomic and Molecular Sciences, Academia
Shreya Choudhary Sinica, Taipei, Taiwan
Department of Biotechnology, RV College of Engineering,
Yoshito Ihara
Bangalore, Karnataka, India
Department of Biochemistry, Wakayama Medical
Steve W Cui University, Wakayama, Japan
Guelph Research and Development Centre, Agriculture and
Yoko Inai
Agri-Food Canada, Guelph, ON, Canada
Department of Biochemistry, Wakayama Medical
Richard D Cummings University, Wakayama, Japan
Beth Israel Deaconess Medical Center, Department of
Yukishige Ito
Surgery, Harvard Medical School, Boston, MA,
RIKEN, Saitama; Graduate School of Science, Osaka
United States
University, Osaka, Japan
Tamara L Doering
Shweta Sudam Kallapur
Department of Molecular Microbiology, Washington
University in St. Louis, St. Louis, MO, United States
Elisa Fadda
Anusha Mysore Keerthi
Department of Chemistry and Hamilton Institute,
Maynooth University, Maynooth, Ireland
Qingbin Guo
Se-Kwon Kim
State Key Laboratory of Food Nutrition and Safety, College
Department of Marine Science & Convergence
of Food Science and Technology, Tianjin University of
Engineering, College of Science & Technology, Hanyang
Science and Technology, Tianjin, China
University Erica, Gyeonggi-do, South Korea
Praveen Kumar Gupta
Yuriy A Knirel
N. D. Zelinsky Institute of Organic Chemistry, Moscow,
Russia
vii
viii List of Contributors for Volume 1
Petra Larsen Raja Mazumder

Department of Chemistry, University of Prince Edward Department of Biochemistry and Molecular Medicine,
Island, Charlottetown, PE, Canada School of Medicine & Health Sciences, The George
Washington University, Washington, DC, United States
Gordan Lauc
Genos Glycoscience Research Laboratory; Faculty of Chi-Kung Ni
Pharmacy and Biochemistry, University of Zagreb, Zagreb, Institute of Atomic and Molecular Sciences, Academia
Croatia Sinica, Taipei, Taiwan
Chia Yen Liew Naohito Ohno
Institute of Atomic and Molecular Sciences, Academia Tokyo University of Pharmacy and Life Sciences, Tokyo,
Sinica, Taipei, Taiwan Japan
Frederique Lisacek Serge Perez
SIB Swiss Institute of Bioinformatics and Faculty of Centre de Recherche sur les Macromolecules Vegetales,
Sciences, University of Geneva, Geneva, Switzerland University of Grenoble Alpes, Centre National de la
Recherche Scientifique, Grenoble, France
Yan Liu
State Key Laboratory of Food Nutrition and Safety, College Marija Pezer
of Food Science and Technology, Tianjin University of Genos Glycoscience Research Laboratory, Zagreb, Croatia
Science and Technology, Tianjin, China
Ashwini Prabhu
Liza C Loza Yenepoya Research Centre, Yenepoya (Deemed to be
Department of Molecular Microbiology, University), Mangalore, Karnataka, India
Washington University in St. Louis, St. Louis, MO,
Vinitha Rani
United States
Yenepoya Research Centre, Yenepoya (Deemed to be
Kelvin B Luther University), Mangalore, Karnataka, India
Department of Biochemistry and Molecular Biology,
Jeffrey S Rohrer
Complex Carbohydrate Research Center, University of
Thermo Fisher Scientific, Sunnyvale, CA, United States
Georgia, Athens, GA, United States
Roberta Salinas-Marín
Thomas Lütteke
Laboratorio de Glicobiologí a y Diagnóstico Molecular,
GIP GmbH, Offenbach, Germany
Centro de Investigación en Dinámica Celular, Universidad
Olga Makshakova Autónoma del Estado de Morelos, Cuernavaca, Morelos,
Kazan Institute of Biochemistry and Biophysics, FRC Kazan Mexico
Scientific Center of Russian Academy of Sciences, Kazan,
David F Smith
Russia
NatGlycan, LLC, Atlanta, GA, United States
Shino Manabe
Xuezheng Song
RIKEN, Saitama; Laboratory of Functional Molecule
Department of Biochemistry, Emory University School of
Chemistry, Pharmaceutical Department and Institute of
Medicine, Atlanta, GA, United States
Medicinal Chemistry, Hoshi University, Tokyo; Research
Center for Pharmaceutical Development, Graduate School Mike Tiemeyer
of Pharmaceutical Sciences & Faculty of Pharmaceutical Complex Carbohydrate Research Center and Department of
Sciences, Tohoku University, Miyagi, Japan Biochemistry and Molecular Biology, University of Georgia,
Athens, GA, United States
Iván Martínez-Duncker
Laboratorio de Glicobiologí a y Diagnóstico Molecular, Shang-Ting Tsai
Centro de Investigación en Dinámica Celular, Universidad Institute of Atomic and Molecular Sciences, Academia
Autónoma del Estado de Morelos, Cuernavaca, Morelos, Sinica, Taipei, Taiwan
Mexico
Marie-Rose Van Calsteren
Marina Martinic Kavur Saint-Hyacinthe Research and Development Centre,
Genos Glycoscience Research Laboratory, Agriculture and Agri-Food Canada, Saint-Hyacinthe, QC,
Zagreb, Croatia Canada
List of Contributors for Volume 1 ix
Jayachandran Venkatesan Jeet Kiran Vora

Yenepoya Research Centre, Yenepoya (Deemed to be Department of Biochemistry and Molecular Medicine,
University), Mangalore, Karnataka, India School of Medicine & Health Sciences, The George
Washington University, Washington, DC, United States
Tania M Villanueva-Cabello
Laboratorio de Glicobiologí a y Diagnóstico Molecular, Göran Widmalm
Centro de Investigación en Dinámica Celular, Universidad Department of Organic Chemistry, Stockholm University,
Autónoma del Estado de Morelos, Cuernavaca, Morelos, Stockholm, Sweden
Mexico
PREFACE
While it is always difficult to categorize a period in history as defined by a unique area of study, the first two
decades of the 21st century can truly be considered a groundbreaking era in Glycoscience. Many researchers,
societies, and governments around the globe have contributed to this, but I will bias this paragraph by listing
three major initiatives in my home country, the United States, that have greatly contributed to this progress:
(1) a “glue grant” from the National Institute of General Medical Sciences of the National Institutes of Health
that led to the formation of the Consortium for Functional Glycomics; (2) a report by the National Research
Council of the National Academy of Sciences entitled “Transforming Glycoscience: A Roadmap for the Future”
that outlined a plan as to where Glycoscience should be in 10–15 years; and (3) the funding of seminal research
to achieve some of these goals by the NIH Common Fund, where grants were awarded to teams of scientists to
advance three seminal areas: (a) Facile Glycan Synthesis; (b) Tool Development for analysis, tracking, and
manipulation of glycans; and (c) data integration and bioinformatics tools to annotate and search all known
glycomes across gene, protein, and lipid data. The timelines for many of these initiatives are expiring, and thus
the timing of this second edition of Comprehensive Glycoscience could not be more appropriate. Although these
programs have reached their natural end, work in this field is continuing at a fevered pitch. These initiatives—as
well as the many unmentioned ones from other countries around the world—have both ramped up excitement
in traditional glycoscientists and ignited interest in those uninitiated to redirect their focus on more
glycan-related chemistry and biology projects.
This second edition of Comprehensive Glycoscience follows a similar pattern as one that shaped the first edition
in 2007, with a few logistical changes. The first edition was comprised of 4 volumes which dealt with
introductory material (nomenclature, glycan composition of various organisms, carbohydrate analysis tech-
niques), glycan synthesis, glycan biochemistry and carbohydrate interactions and glycans in disease. Since the
field has made major strides in the past 14 years, many of the original authors were asked to update their
chapters, while many new researchers were asked to contribute. This second edition has expanded to 5 volumes,
all with very focused content. Volume 1 sees some of the introductory material deleted, while focusing on new
advances in glycomics and carbohydrate analysis in 21 chapters. The 24 chapters of Volume 2 are dedicated
entirely to synthesis: Basic and modern glycosylation methods, protecting groups, synthesis of various sugar
types such as sialic acids and furanoses and several articles on the newly minted use of automation in
carbohydrate synthesis. Volume 3 is outlined similar to the first edition, with 22 chapters where subjects of
high research interest in the intervening years have been included, such as O-GlcNAc chemical biology,
metabolic engineering of glycans, and zwitterionic polysaccharides. Volume 4 is a new volume, with its
22 chapters dedicated to glycan materials, nanoparticles, and arrays. Very little of this subject material was
covered in the first edition, and it was decided to dedicate an entire volume to the subject, where much of this
research was in its infancy in 2006–07. Chapters on polymeric and metallic nanomaterials, glycopolymers
themselves and their applications, various array formats that have been developed, glyconanomaterials in
biosensing, and applications of these constructions to treating diseases are presented. Volume 5 is comprised
of 31 chapters on the functions of glycans in disease, with highlights on bacterial infections, neurological
disorders, IgG glycosylation, and immune effector functions along with two articles that describe the use of
human milk oligosaccharides in therapeutic applications.
The goal of this edition was not to simply update the first edition but to focus on the phenomenal
achievements that have advanced Glycoscience since the initial printing. While there are a similar number of
chapters, the content is more targeted to these advancements and to hopefully inspire the next generation of
glycoscientists. Thus, although there is a teaching element to this second edition, it is more geared toward the
xi
xii Preface
advanced undergraduate or graduate student who may be involved in a “glyco”-related science or has the
background to understand the concepts and who may be drawn into this highly intriguing and still somewhat
fledging field. The established professor or investigator should find this series a welcome addition to their
collection and will beautifully complement other treatises in glycoscience. The content, along with the
comprehensive list of references, should ground virtually any researcher with a foundation to explore and
expand this exciting area.
Lastly, it should be noted that the bulk of this edition has been assembled in the middle of once-in-100-years
pandemic. COVID-19 has affected all our lives in mostly detrimental ways, and it is a true testament to the
publisher, the editors, and the authors of the 120 chapters who all have fought through unprecedented adversity
to see this project to completion. I owe all involved a debt of gratitude that a project of this scope could be
completed under these unusual circumstances.
Joseph J. Barchi, Jr.

Editor in Chief
CONTENTS OF VOLUME 1
1.01 Introduction to Comprehensive Glycoscience: The Good, the Better and What's to Come 1
Joseph J Barchi Jr
1.02 Bacterial Exopolysaccharides 21

Yuriy A Knirel and Marie-Rose Van Calsteren
1.03 Fungal Polysaccharides 96

Naohito Ohno
1.04 Seaweed Polysaccharides: Promising Molecules for Biotechnological Applications 131

Vinitha Rani, Ashwini Prabhu, Jayachandran Venkatesan, and Se-Kwon Kim
1.05 Common Cellular Glycans: Biosynthesis, Modifications and Functions in Cancer and
Inflammation 142
Petra Larsen and Marya Ahmed
1.06 C-Mannosyl Tryptophan: From Chemistry to Cell Biology 163

Yoshito Ihara, Shino Manabe, Yoko Inai, and Yukishige Ito
1.07 O-Fucosylation of Proteins 182

Kelvin B Luther and Robert S Haltiwanger
1.08 Structure, Classification and Modification of Polysaccharides 204

Qingbin Guo, Yan Liu, and Steve W Cui
1.09 Overview of Cellulose Types and Applications 220

Praveen Kumar Gupta, Anusha Mysore Keerthi, Shweta Sudam Kallapur, and Shreya Choudhary
1.10 Mucins: Structure and Function 237

Roberta Salinas-Marí n, Tania M Villanueva-Cabello, and Iván Martí nez-Duncker
1.11 High-pH Anion-Exchange Chromatography (HPAEC) and Pulsed Amperometric

Detection (PAD) for Carbohydrate Analysis 266
Mark R Hardy and Jeffrey S Rohrer
1.12 Capillary Electrophoresis 290

Lisa A Holland and C Eugene Bennett
1.13 Modern Mass Spectrometry Techniques for Oligosaccharide Structure Determination:

Logically Derived Sequence Tandem Mass Spectrometry for Automatic Oligosaccharide
Structural Determination 309
Chi-Kung Ni, Hsu Chen Hsu, Chia Yen Liew, Shih-Pei Huang, and Shang-Ting Tsai
1.14 General NMR Spectroscopy of Carbohydrates and Conformational Analysis in Solution 340
Göran Widmalm
1.15 Computational Modeling in Glycoscience 374

Serge Perez, Elisa Fadda, and Olga Makshakova
1.16 Understanding the Structure and Function of Viral Glycosylation by Molecular Simulations:
State-of-the-Art and Recent Case Studies 405
Elisa Fadda
xiii
xiv Contents of Volume 1
1.17 Tools and Methods to Study the Human Glycome 416

Xuezheng Song, Richard D Cummings, and David F Smith
1.18 Glycosciences.de: Databases and Tools to Support Research in Glycomics and

Glycoproteomics 432
Thomas Lütteke
1.19 Systems Glycobiology: Immunoglobulin G Glycans as Biomarkers and Functional

Effectors in Aging and Diseases 439
Marina Martinic Kavur, Gordan Lauc, and Marija Pezer
1.20 Glycans of the Pathogenic Yeast Cryptococcus neoformans and Related Opportunities
for Therapeutic Advances 479
Liza C Loza and Tamara L Doering
1.21 Glycoinformatics Resources Integrated Through the GlySpace Alliance 507

Frederique Lisacek, Kiyoko F Aoki-Kinoshita, Jeet Kiran Vora, Raja Mazumder, and Mike Tiemeyer
PERMISSION ACKNOWLEDGEMENT
The following material is reproduced with kind permission of Oxford University press
Figure 2 of Glycan-based Materials in Cancer and Inflammation
Table 1 of Glycan-based Materials in Cancer and Inflammation
www.oup.com
The following material is reproduced with kind permission of Nature Publishing Group
Figure 29 of Surface Immobilized Glycopolymers
Figure 11 of Controls on Element Partitioning Behavior
Figure 5 of Overview of Cellulose Types
Figure 19 of Molecular and Mechanistic Basis of Lectin-glycan Interactions
Figure 6 of Overview of Cellulose Types and Applications
Figure 11 of Capillary Electrophoresis
Figure 8 of Glycan-based Materials in Cancer and Inflammation
http://www.nature.com
i
1.01 Introduction to Comprehensive Glycoscience: The Good, the Better and
What’s to Come
Joseph J Barchi Jr, Head, Glycoconjugate and NMR Section, Chemical Biology Laboratory, Center for Cancer Research, Frederick, MD,
United States
© 2021 Elsevier B.V. All rights reserved.
1.01.1 Introduction 1
1.01.1.1 Brief history of glycoscience 2
1.01.1.2 What are carbohydrates/glycans and what do they look like? 2
1.01.2 Analysis of glycans 9
1.01.2.1 High pH anion-exchange chromatography (HPAEC) and pulsed amperometric detection (PAD) 9
1.01.2.2 Capillary electrophoresis (CE) 9
1.01.2.3 Mass spectrometry 9
1.01.2.4 NMR spectroscopy and molecular simulations 10
1.01.3 Glycan synthesis 11
1.01.4 Cellular glycan functions 12
1.01.4.1 Glycan binding proteins 12
1.01.4.2 Glycans in disease 14
1.01.5 Summary and perspective 15
Appendix 16
References 16
1.01.1 Introduction
Although scientific studies of sugars date back hundreds of years, one could posit that the past three decades constitutes what could
be considered the “new era” of Glycoscience, where appreciation of the relevance of cellular carbohydrates is now indelibly stamped
in the mindset of both physical and life scientists. In fact, a search of the literature reveals that the word “Glycoscience” has only
been coined within those last 30 years with the first instance of the term coming (arguably) around 1994.1 The biology and
chemistry of carbohydrates had traditionally been relegated to a few select and highly specialized research groups that were bold
enough to tackle the complexities of this family of biomolecules. And complex they are: Oligo- and polysaccharides encompass
more “information density” than the other essential cellular information stores of nucleic acids, proteins and lipids.2–5 The
challenges with the analysis, structure, synthesis and biochemistry of cellular carbohydrates is aptly summarized in the forward
to an issue of Chemical Reviews, published in 2000. In it, James K. Bashkin writes6:
“I believe it was George Bernard Shaw who was asked if he knew that “sugar” was the only word in the English language where “su” was pronounced
“sh”. He replied, “Sure”. Sugars remain ubiquitous yet enigmatic, combining the simple with the complex. Carbohydrates are everywhere, from bulk
sucrose in the kitchen to cross-linked peptidoglycans that comprise cell walls, from microdiverse, posttranscriptionally modified cell-surface receptors to
the paper that this issue is printed on. Carbohydrates have often been relegated to the sidelines of chemistry, one example being the complete omission
of essential and challenging sugar portions from many papers on “natural product synthesis.” One can almost hear the collective sigh, “Difficult
chemistry, difficult biology, difficult analysis, I don’t want to see another protecting group, let’s leave the sugar off.”
It seemed that many in the research community thought that sugars just “gum up the works” and studying them made one’s life
difficult. In the early days of protein isolation and purification, sugars were enzymatically stripped off to insure better purity and
ease of handling. When recombinant expression of proteins came of age, the bacteria used for production, primarily E. coli, lacked
glycosylation machinery and hence proteins were produced without any covalent attachment of any post-translational oligosac-
charide chains. This certainly did not upset those working with these proteins, as it made purification and analysis much simpler.
Little did they understand the importance of many of these oligosaccharide chains that, had they been present, could not only
modulate, but actually dictate the function of that particular macromolecule. The research community has come to realize the
overarching importance of cellular glycosylation and today the field of Glycoscience has taken its rightful place among other
scientific disciplines that for years had overshadowed the relevance of cellular and naturally occurring mono-, di-, oligo- and
polysaccharides. There is a fevered interest in most all areas of glycosciences today, including, but not limited to: (1) Glycomics,7,8
the analysis of the full repertoire of the glycans of a particular cell type, which necessitated the development of the new field of
“Glycoinformatics”9,10; (2) glycan synthesis, both chemical and enzymatic, to allow access to all types of both eukaryotic and
prokaryotic saccharides that are known or will be through developments in area #1, (3) technology development, such as the design
and development of glycan/lectin arrays and spectroscopic techniques for glycan analysis and (4) advancement of glycan engineer-
ing techniques for both medical and biotechnology-related applications.
Comprehensive Glycoscience, 2nd edition https://doi.org/10.1016/B978-0-12-819475-1.00108-5 1

2 Introduction to Comprehensive Glycoscience: The Good, the Better and What’s to Come
1.01.1.1 Brief history of glycoscience

As can be inferred from the above discussion, Glycoscience research is a very vibrant field of study. Hence, the number papers and
reviews related to glycoscience has also expanded greatly in the intervening years since the first edition of the Comprehensive
Glycoscience series was published in 2007. There have been a number of books and monographs written on the subject which the
reader should refer to for detailed background information. A list of these are available at the end of this article. An excellent
reference guide to most all aspects of glycoscience is “Essentials of Glycobiology, 3rd edition” which can be found free of charge at
the National Center for Biotechnology Information.11
A quick SciFinder search (Fig. 1) shows the increase in publications with the term “Glycoscience” as the search criterion, with the
highest frequency in the past decade. Alternatively, the word “Glycan,” which seems to have originated in the literature in the late
1940s, has had a precipitous rise in usage and publications with the term in the title, abstract or keyword. In addition, Glycomics,
the study of the “Glycome” (the complete repertoire of glycans produced and presented by a specific organism) took flight just as the
human genome was revealed in 2000. A seminal editorial by Hirabayashi and Kasai, and possibly the first use of the word glycomics
in the literature, suggested that a field be started to define the full set of glycans in different organisms.12 They argued that the study of
glycans, being the third set of important biomolecules after nucleic acids and proteins, was essential to fully understand the function of
the genome and hence, the proteome. This was a truly prescient article that even outlined a bulleted plan as how the field of glycomics
could take shape. Since that time, no fewer than 2400 articles have the word “glycomics” included in the title or abstract. The reader is
referred to chapters by Smith (Chapter 1.17) and Lauc (Chapter 1.19) for a modern discussion of glycomics and the techniques used in
the field. Table 1 lists a few of the early discoveries in carbohydrate/glycoscience that set the stage for the vibrant field it has become.
The exponential growth in research related to an ever-widening breadth of Glycoscience-related topics has consequently led to
a concomitant rise in reviews, treatises and book series on these subjects. The seminal review published in 1993 by Varki suggested
that, regarding the biological roles of oligosaccharides, “all the theories are correct.”13 That is, the roles of saccharides ran the gamut
from trivial to essential in many biological systems, and while many roles are operational, exceptions to all of these are also found.
An update to that review published in 2017 recapitulated this argument, while bringing the idea up to a modern and expanded
version of its original self. As should now be evident, a “comprehensive” review of the field is beyond the scope of any series; and
while both reviews had over 1000 references, it was stated that in the 2017 version that “only a few examples will be cited”!14 Thus,
although one could ask “why write another one,” the previous sentence makes the answer obvious: Keeping pace with this field
warrants frequent and detailed refinements since it is now officially considered part of the mainstream of both the physical and
biological sciences.
The remainder of this section will very briefly introduce the structures of sugars for the uninitiated and continue to the describe
the progressive accomplishments in the fields of Glycoscience as they relate to the chapters here in the second edition of this series.
Brevity will be the operative word here; every effort will be made to refer concepts represented in this introductory chapter to
an appropriate chapter in one of the 5 volumes of this updated series.
1.01.1.2 What are carbohydrates/glycans and what do they look like?

Carbohydrates, in various presentations, are present in all cells from all phyla and species. The word carbohydrate (or as are used
interchangeably: sugar, glycan and saccharide) derives from “carbon” and “hydrate” as all carbons of (most) sugars are “hydrated”,
i.e., contain the elements of water (H-OH). Hence, the formula can be written as such; Cn(H2O)n. Emil Fischer is often cited as the
“father” of carbohydrate chemistry, since it was Fischer who is credited with elucidation of the structure of glucose. The determi-
nation of glucose stereochemistry was a monumental achievement at the time, and a brilliant treatise on the steps involved in this
determination, as well as other sugars such as mannose, galactose and arabinose have been detailed by Claude S Hudson in a series
of papers from 1935–48.15–18 A wonderful account and centennial testament to his research was written by Lichtenthäler in
1992.19,20 The structure of glucose in its various forms is shown in Fig. 2.
Fischer depicted the hexose in a straight vertical chain with the aldehydic carbon on top. This presentation could be thought of
as the carbon chain “bowing into” of the plane of the paper (right structure in the blue box). These views are termed projections,
Fig. 1 Rise in the publications with the word “Glycoscience” (A) and “Glycan” (B). The graph in B extends back to 1894 since the search engine in Scopus
evidently equates the word “polysaccharide” with “Glycan”. The word glycan does not actually enter the scientific literature lexicon until about 1943.
Introduction to Comprehensive Glycoscience: The Good, the Better and What’s to Come 3
Table 1 A few of the early discoveries in carbohydrate/Glycoscience that set the stage for the vibrant field it is today.
Scientist (country of origin) Notable Discovery Year
Andreas Sigismund Marggraf (Germany) Discovered sucrose from sugar beets; Glucose from raisins 1747
Jean Baptiste André Dumas (France) Coined the term “glucose” (from the Greek for sweet) 1834
Jacobus Henrikus van’t Hoff (Netherlands) Proposed the concept of the tetrahedral carbon 1874
Nobel Prize in Chemistry 1901 Chirality, stereochemistry
Joseph Achille Le Bel (France)
Bernhard Tollens (Germany) Recognized the cyclic hemiacetal form of carbohydrates 1883
Emil Fischer (Germany) Determined the molecular structure and stereochemistry of glucose, and other sugars 1891
Nobel Prize in Chemistry 1902
Sir Walter Norman Haworth (United Kingdom) Structure and synthesis of ascorbic acid; novel way of drawing carbohydrate cyclic forms 1933
Nobel Prize in Chemistry 1937
Carl Cori and Gerty Cori (USA) Metabolism of glucose; Determined how the body produces and stores energy 1920’s, 1930’s
Nobel Prize in Physiology and Medicine 1947
Luis Leloir (France) Discovery of sugar nucleotides and their role in the biosynthesis of carbohydrates 1949
Nobel in Chemistry 1970 (Prize in 1970)
Morgan and Watkins Discovery that ABO blood group antigens are sugars 1969
Fig. 2 Glucose as represented by a Fischer projection, Haworth projection and in three-dimensional forms that are primarily shown in the literature. The pyranose
form is a 6-membered ring whereas the furanose ring is 5-membered.
as they involve squashing a dimensional molecule onto a two-dimensional page. Most textbooks will initially use a Fischer
projection to differentiate between “D” and “L” sugars. Looking at the Fischer projection, the stereogenic carbon atom furthest
from the carbonyl carbon traditionally defined “D” glucose as the molecule with this hydroxy group to the right (Fig. 2, blue square)
and “L” with the hydroxyl pointing to the left. It should be noted that this now somewhat archaic description was based on the
arbitrary glyceraldehyde stereochemistry assigned by Rosanoff and this nomenclature was later referred to as the Fischer-Rosanoff
convention.21 Since “D” and “L” glucose (and any other D and L pair for that matter) are enantiomers, all the stereocenters need to be
reversed to produce “L” glucose, not simply C-5.
If one rotates the molecule 90 degrees to the right and curls the carbon chain to allow proximity of the 5th hydroxyl (counting
from the carbonyl carbon) to the aldehyde, it becomes evident how the hemiacetal carbon can be formed. This yields the Haworth
projection in the yellow box. Sugars are often depicted in the literature in this form, although the three-dimensional representation
shown in the lower half of Fig. 2 is more akin to a true Organic Chemistry structure where the stereochemistry of the carbon atoms
can easily be seen. The stereochemistry of the hemiacetal hydroxyl group can be either up (beta) or down (alpha) in what is referred
to as a “reducing sugar.” This designation comes from the fact that the aldehyde can act as a “reducing agent” toward entities such
as metals; this property is the basis for the Tollens test, where silver salts are reduced to elemental silver with simultaneous oxidation
of the reducing sugar aldehyde to a carboxylic acid.22–24
As mentioned above, carbohydrates are found on all cells from both eukaryotic and prokaryotic organisms. The sets of
carbohydrate structures that are biosynthesized and presented on cell surfaces between different species can differ dramatically.
Thus, the aforementioned complexities of sugars structures compared with nucleic acids and peptides comes from the following
facts: (1) there are actually 100s and predicted to be 1000s of structurally unique monomeric sugars that span all organisms from
bacteria to humans as opposed to 5 bases that comprise DNA and RNA and 21 natural amino acids that form most proteins; (2) the
anomeric center can exist in two epimeric forms; (3) all sugars have more than one functional group that can be modified/
conjugated. This makes the diversity of carbohydrate structures infinitely more complex than the simple connections that are made
between two amino acids to form peptides or two DNA/RNA base pairs to form a dinucleotide. Glucose is an example of
a monosaccharide, i.e., “one sugar unit.” This can be extended to di-, tri-, tetra- and what are considered “oligo”-saccharides
which constitute up to 10–20 monosaccharide units. Beyond that, these coupled chains are can now be considered
“poly”-saccharides (for example, cellulose and chrysolaminarin, are polymers of glucose, and are arguably the most abundant
materials on earth).25 Consider that a simple glucose monosaccharide contains five hydroxyl groups in five chiral centers, and
a choice of either an alpha or beta anomeric center. If you had 20 pyranose glycan units similar to glucose, and compared the
combinatorial number of hexamers that could be constructed compared to those from 4 nucleotides (46 ¼ 4096) or 20 natural
amino acids (206 ¼ 64,000,000), a total of 192,780,943, 360 hexasaccharides are possible.5 The information content in carbohy-
drate monomers and oligomers is truly vast and as yet, not fully appreciated (vide infra).
Descriptions of glycans from all species is beyond the scope of this article, thus, groups of various saccharides that are more
common in mammalian, plant and bacterial systems will be briefly discussed. It is generally recognized that there are 10 (the
number may be 11 or 12) basic mammalian sugar building blocks that are used to assemble the various cellular glycans that have
thus far been determined.4 These are shown in Fig. 3 with their standard abbreviations. The six-membered pyranoses are thought to
exist in a typical chair conformation that was learned from cyclohexane structures. In sugars, there is a notation that describes the
spatial relationship of atoms in a particular form. As shown in the figure, a “4C1” chair has Carbon-4 puckered “up” out of the
central plane that would bisect each bond, and the C-1 atom flexed “down.” Alternatively, a “1C4” pucker (fucose) has those atoms
Fig. 3 The 10 most common mammalian monosaccharides used to construct various cellular glycans and their abbreviations in parentheses. Numbering and
puckered forms are in colored numbers and circles.
flipped between up and down. As opposed to all other in the diagram, fucose is the only L-sugar. Sometimes one may see the
notation written “4C1” since that more accurately shows where the atoms are in space. N-Acetylneuraminic acid, more commonly
known as sialic acid, is a 9-carbon sugar acid were the carboxylate group is pointed “up” while the pyranose is in a “2C5” pucker,
since the numbering of this 9-carbon sugar starts at the carboxyl carbon (see bottom of Fig. 3).
These monosaccharides make up most of the glycans that are displayed on the surface (or now, within) a mammalian cell.
Cell-surface glycans are presented in a variety of forms, each with their own structural idiosyncrasies and dispositions. One of the
best depictions of this is from the introductory sections of “Essentials of Glycobiology” thus there is no need to reinvent this figure.
This schematic of the cell surface glycocalyx, as it is often called, is adapted and modified in Fig. 4 for this article. It shows in generic
form, the various structures that would be found, for example, on one of the cells of human tissue. Either the initial (reducing end)
sugar or the entire structure of each entity is illustrated for each type of glycan and arrows point to either the macromolecule, lipid or
polymer whose context that structure is associated. A listing of how these structures are arranged are as follows, and the chapters that
discuss the various roles these modifications play in biological function or disease in this series are shown in parentheses:
1. N-Linked glycans: Attached to asparagine in specific amino acid triplet motifs of Asn-Ser/Thr-X, where X ¼ any amino acid
except proline. b-Amide-linked anomeric center to a chitobiose unit (i.e., -GlcNAcb1,4-GlcNAcb-N-CO-CH2-amino acid)26 (Gu,
Chapter 5.25)
2. Glycolipids: Glycans from mono- to oligosaccharides attached to a lipid, can be a glycerol, sphingosine or ceramide unit.
Most contain a reducing end b-glucose, some with b-galactose. Can have varied composition of sugars based on cell and species
of origin.27 (Schnaar, Chapter 3.05, Savage, Chapter 3.22)
3. O-Linked mucin-type glycosylation: Glycans attached to either serine or threonine on cell-surface mucins through an initial
a-Galactosamine monomer; glycans can be anywhere from 2–12 monosaccharides, When “O-linked” saccharides are discussed,
it usually refers to this type of protein glycosylation. (Brockhausen, Chapter 3.10, and Ramirez, Chapter 1.10)
4. O-GlcNAc modification: Discovered about 30 years ago. widespread modification of cytoplasmic and nuclear proteins.
Molecular “switch” similar to phosphorylation but only one transferase and hydrolase known for attaching and releasing
the modification. (Hart, Chapter 5.08; Zachara, Chapter 3.13 and Jiang, Chapter 3.06)
5. C-Mannosyl tryptophan: Thought to be a unique protein modification and the only natural carbon-linked glycan known where
an a-mannose attaches to the indole C2 carbon atom of a tryptophan amino acid. Usually attached at a consensus sequence W-x-
x-W.28 (Ihara, Chapter 1.06)
6. Glycophosphatidylinositol (GPI anchor): Complex lipid/inositol glycan that anchors various proteins to cell membranes.
A phosphatidylinositol lipid embeds in the membrane with core glycans that comprise one glucosamine and three mannoses;
the terminal non-reducing end mannose contains an O6-linked phosphoethanolamine, which is amide-bonded to the carboxyl
terminus of a protein. Common form of cellular protein attachment in Protozoa. (Fujita, Chapter 3.04 and Murakami,
Chapter 5.21)
7. O-Fucosylation (O-glucose, O-mannose): Discovered around 1993, O-fucose and fucosylated glycans are a-linked to serine and
threonine residues and found on Epidermal Growth Factor (EGF) repeats on several proteins and occurs in a putative consensus
sequence (CXXGG(S/T)C, where S/T is the modified residue. These along with O-glucose and O-mannose have been found on
thrombospondin-type repeat protein motifs. O-Mannose is found highly concentrated in brain glycoproteins. (Haltiwanger,
Chapter 1.07)
8. Glycosaminoglycans (GAGs): Charged, sulfated, long linear polysaccharide chains primarily attached to proteins. Chondroitin
sulfate, dermatan sulfate, keratan sulfate and heparan sulfate are typical GAGs. Attached to proteins through a serine hydroxyl
with a consensus Ser-Gly/Ala-X-Gly motif in the core protein. A tetrasaccharide linker, -GlcAb1,3Galb1,3Galb1,4Xylb1-O-(Ser)-
begins the construction of the linear polysaccharide. The polysaccharides are built from disaccharide repeats that usually consist
of a sugar acid and an amino sugar. Proteins heavily glycosylated with GAGs are referred to as Proteoglycans. (Ramirez,
Chapter 3.03; Kitagawa, Chapter 3.02 and Liu, Chapter 2.24)
9. Hyaluronic acid (Hyaluronan): A GAG that is biosynthesized but immediately secreted into the intercellular space, thus not
formally a surface modification, and not covalently attached to proteoglycans. It is a component of the extracellular matrix.
(Kitagawa, Chapter 3.02)
Many of these glycans, especially N- and O-linked glycans, are structurally complex, where linear chains are built of many different
monosaccharides, and branching and “capping” (vide infra) are common where additional multi-antennae arrangements are
possible. Often, a single glycosylation site will be dynamically occupied by different oligosaccharides that may differ by one or
more monosaccharides. These different glycans at one site are called “glycoforms,”29,30 and it is obvious how this adds to the almost
overwhelming complexity of cellular glycosylation. The presence of various glycoforms results from the differential expression of
glycosyltransferases (enzymes that couple one sugar to another) and glycoside hydrolases (enzymes that cleave a sugar from
a oligosaccharide) that can arise in a tissue-, organ-, temporal- or spatial-specific manner. The presence of glycoforms is one of the
many ways to rationalize the “underwhelming” result of mapping the human genome. It surprised everyone when it was discovered
that we only harbor 21,000 protein-encoding genes, where the thought was closer to 100,000 in early estimates.31 However, the
one-gene/one-protein model is a gross oversimplification; alternative splicing can generate many proteins from a single gene and
post-translational modifications (phosphorylation, farnesylation, acylation, alkylation, sulfation and glycosylation, just to name
a few) can impart “fine-tuning” of functions to a single protein. These and many other changes that take place during development
can lead to a complex organism from a relatively small number of coding sequences.
6
Introduction to Comprehensive Glycoscience: The Good, the Better and What’s to Come
Fig. 4 A schematic of the various glycan forms that are primarily displayed on a mammalian cell surface along with nuclear/cytoplasmic O-GlcNAc, as adapted from “Essentials of Glycobiology”, third edition, Chapter 1,
Fig. 1.6. The carbohydrate structures that begin a particular glycan are shown for mucin type O-linked glycosylation (upper left, a-D-Galactosamine), N-linked glycosylation (chitobiose structure) and glycolipids (b-glucose
attached to a ceramide lipid). Also depicted is the disaccharide repeating unit of hyaluronic acid (hyaluronan, -GlcAb1,4GlcNAc-), glycosaminoglycan; b-O-GlcNAc, a prominent modification to nuclear and cytoplasmic proteins;
an entire structure of a glycophosphatidylinositol (GPI anchor), a complex, charged glycolipid that is an important connector between the cell membrane and various cell-surface proteins and the sole C-linked glycan modification,
C-mannosyl tryptophan, that is found in motifs containing the WxxW tetrapeptide stretch in proteins. Originally modified and updated from Varki, A. FASEB J. 1997, 11: 248–255; Fuster, M; Esko, J.D. Nat. Rev. Cancer 2005, 7,
526–542, originally with permission from Macmillan; and Stanley P. Cold Spring Harb. Perspect. Biol. 2011, 3, a005199.
Without explicitly depicting the many glycan variants, on perusing Fig. 4, the reader can imagine how complicated the cell
surface can be with the presence of 1000s of proteins each with their own glycosylation network. In addition, since the cell is
utilizing a vast amount of energy to assemble these complex structures, it follows that there must be some highly relevant functions
that these modifications impart to proteins and lipids (vide infra).
Whereas these structures make up the majority of the glycans in many eukaryotic glycomes, various database and bioinformatic
analyzes of bacterial glycomes suggest that there are over 700 different monosaccharides that are used to biosynthesize the
incredibly diverse array of glycans in bacteria species.32 In fact, a variety of unusual sugar structures come from organisms other
than humans and other mammals. Many of these structures are not six-carbon hexoses, but glycosides made up of different
numbers of carbon atoms from pentoses (5-carbon) to nonoses (9-carbon) and even longer. As the complexity of the glycan
repertoire grew, the early full chemical drawing depictions of sugars was thought to have become somewhat unwieldy. As early
as 1978, Kornfeld proposed a simplified presentation of the various sugar structures based on geometrical shapes, thought to be
a purposeful substitute for full stereochemical drawings. Future incarnations of this new mode of glycans representation matured
to what is now known as the Symbol Nomenclature for Glycans (SNFG).33 This code is evident in Fig. 4 with a small legend at the
bottom left. Many papers in the Glycoscience field will use this notation, as it has been used throughout this 2nd edition of
Comprehensive Glycoscience. Fig. A.1 that shows the latest listing of symbols to represent a large array of glycans is shown in the
Appendix section.
Bacteria, fungi and plants contain a rich array of glycans with monomer structures that vary from those in higher organisms.
Some of the more relevant monosaccharides are higher carbon (8- and 9-carbon) sugars. One of these structures, 3-deoxy-D-
manno-octulosonic acid (Kdo), is a component of the lipopolysaccharide portion of the outer surface of gram-negative bacteria.34
This extended covalent unit of lipids and sugars is referred to as endotoxin, and Kdo is attached to a portion called Lipid A. Lipid A is
released from the bacterium after infection or lysis in serum and is a powerful biological response modifier, and this glycosylated
assembly has been one of the more intensely studied portions of the bacterial cell membrane. This complicated glycolipid is a signal
to turn on aspects of the immune system that cause inflammation and other symptoms of a bacterial infection. Further study
revealed that Kdo is thought to be important for bacterial cell viability and survival. A schematic of the composition of the inner and
outer membrane structures from gram-negative bacteria are shown in Fig. 5.35 Examination of panels A, B and C shows increasing
detail as to the structure of LPS and its toxic component, Lipid A. Glycoscientists have learned an enormous amount about
saccharide biosynthesis, assembly and function through work on bacteria. As stated, there are a plethora of unusual sugars presented
in bacteria, and thoughts about their evolution and function have spurred additional work where for example, new synthetic and
analysis techniques have been developed. The reader is referred to excellent chapters by Brockhausen (Chapter 3.07), Molinaro
(Chapter 5.13), and Knirel (Chapter 1.02) for details of the structure and virulence of bacterial saccharides.
Bacteria have evolved to produce a variety of different glycans with modifications such as deoxygenation of different hydroxyl
groups, hydroxyl-to-amine substitutions, many L-sugars and stereochemically unique arrangements of functional groups.
Fig. 5 (A) Schematic depiction of the outer and inner membrane of gram negative bacteria; (B) an expansion of the features of the lipopolysaccharide (LPS) portion
of the outer membrane in a molecular schematic form, and (C) a further expansion of the lipid A portion of LPS in pictorial form (top), molecular schematic (middle)
and molecular formula form (bottom). Figure was derived from Zamyatina, A. Aminosugar-Based Immunomodulator Lipid A: Synthetic Approaches. Beilstein J. Org.
Chem. 2018, 14, 25–53.
Fig. 6 Sampling of some unusual saccharides found in various species of bacteria.
An extremely small sampling of the interesting diversity of bacterial saccharides is shown in Fig. 6. Both enantiomers of fucosamine
are found in gram negative bacteria.36,37 The deoxy-gulose molecules are found in bacteria but also are glycan constituents of cardiac
glycosides found in plants, most often the Foxglove species.38 Altrose is found in certain anaerobic bacteria strains such
as Butyrivibrio fibrisolvens strain CF3.39 Glycero-mannoheptoses are common constituents of the LPS core region saccharides from
a variety of bacterial species.40–46
A few words should be said about sialic acids. This 9-carbon sugar is a common glycan found in all vertebrates and has myriad
functions in cells. Referring to Fig. 4, most N- and O-linked glycans in normal cells will be “capped” by sialic acids; this final
addition to a glycan instructs the cell to stop conjugating additional sugars to the formed glycan. In addition, this adds a large
negatively charged coat to the cell surface that has defined effects on cellular properties.47 There are more than 50 sialic acid analogs
known to date across many species.48 Some are also found in bacteria such as those depicted in Fig. 7. These structures illustrate
the diverse biosynthetic pathways that are taken in bacteria as opposed to higher organisms. While Kdn, the “5-deaminated” version
of Neu5Ac, has been found both in bacteria and higher animals, pseudaminic, legionaminic and acinetaminic acids are all found in
bacteria.49
It should be noted that of all the major groups of biological macro/molecules that make up the composition of every cell—
nucleic acids, proteins, carbohydrates and lipids—each one either embodies or is associated with glycan structures: Base pairs of
nucleic acids are composed of a pyrimidine or purine base and a ribose (RNA) or deoxyribose (DNA) ring; the most abundant
post-translational modification of a protein is glycosylation and lipids can be of many forms, including highly important
glycolipids.
To date, the study of cellular glycans has shown that they are present on all cells, from every domain from Archaea—Bacteria—
Eukarya. Thus, we most likely have only scratched the surface of the number and types of glycans that are biosynthesized by various
Fig. 7 Analogs of sialic acid found in various species of bacteria.

organisms. This introduction serves to ground the reader for further exploration into glycans from their organism of choice. Further
reading in this series will find chapters dedicated to seaweed polysaccharides (Kim, Chapter 1.04), Mucin type (Brockhausen,
Chapter 3.10), yeast and fungal polysaccharides (Ohno, Chapter 1.03), bacterial exopolysaccharides (Knirel, Chapter 1.02),
nucleocytoplasmic protein glycosylation (Jiang, Chapter 3.06), bacterial zwitterionic polysaccharides (Andreana, Chapter 3.21),
vertebrate N-linked glycans (Suzuki, Chapter 3.01), Proteoglycans and GAGs (Ramirez, Chapter 3.03 and Kitagawa, Chapter 3.02),
Protozoan glycans (McConville, Chapter 3.08), Drosophila melanogaster (Nishihara, Chapter 5.01), Caenorhabditis elegans (Wilson,
Chapter 5.02), plant glycans (Misaki, Chapter 5.05) and human milk oligosaccharides (Garrido, Chapter 5.23 and Urashima).
1.01.2 Analysis of glycans
It may seem obvious from the above discussion that isolating pure glycans, analyzing their composition, determining monomeric
structures, correct linkages and stereochemistry is a daunting task. Many traditional methods are still used today and updates to
instrumentation and experimental techniques have allowed higher resolution and extension to different glycans. Newer analytical
tools and modernization and adaptation of existing tools has allowed carbohydrate analysis and glycomics research to take some
very large leaps in the years since the first edition of this series. This section will very briefly touch on primary analysis methods and
the discovery of some new methods to facilitate cellular glycan structure determination. Some of the unique challenges that the field
is attempting to address are:
1. Monomer separations
2. Oligosaccharide composition
3. Glycoforms
4. Linkage analysis
5. Low abundance of glycosylated proteins (sensitivity)
6. Specificity of reagent probes
7. Reagents for efficient release of various glycan types (O-linked, N-linked)
8. No simple sequencing procedures, unlike nucleic acids and proteins
A few examples from this series are briefly mentioned below.
1.01.2.1 High pH anion-exchange chromatography (HPAEC) and pulsed amperometric detection (PAD)
This technique has been available for more than 4 decades and is still a method of choice for the separation and detection of
carbohydrates.50,51 There are several challenges to carbohydrate analysis but one major for chromatography is there is no distinct
chromophore for simple UV detection at standard wavelengths. HPAEC-PAD is based on the property that carbohydrates are weak
acids and ionize at high pH. Carbohydrates are run through an anion exchange column where separation can be achieved at high
pH. Carbohydrates are also electrochemically active, that is they contain functional groups that can be oxidized (anomeric position,
hydroxyls, see Tollens test, vide supra). The effluent of the column can be sent to detector where a voltage is applied across electrodes;
a change in current occurs when an analyte is oxidized or reduced, facilitating detection of the separated sugars. The chapter 1.11 by
Rohrer outlines the process in an update to his chapter from 2007.
1.01.2.2 Capillary electrophoresis (CE)

This technique is based on the motion of analyte particles relative to a flow fluid under the influence of an electric field. This has
been used for carbohydrate analysis and quality control applications in the pharmaceutical industry for many years.52–56 This
technique could be thought of gel electrophoresis transferred to a narrow bore capillary. This in turns increases resistance, allowing
the use of lower electric current for separation and a higher voltage to be applied resulting in increased separation efficiency and
lower run times. Often, unlabeled carbohydrates will be tagged with a fluorescent moiety, usually attached at the reducing end, to
facilitate detection.57 In the last several years, CE has been coupled to mass spectrometry for simplified and high resolution
detection and identification of carbohydrates.58–64 Chapter 1.12 by Holland in this series is a thorough review of this technique
with applications to modern carbohydrate analysis.
1.01.2.3 Mass spectrometry

Probably the most important and relevant technique for glycomics/glycoproteomic studies, and one that has advanced more than
many others in the past 15–20 years is mass spectrometry.58,59,61,65–88 “Mass spec” (MS) is highly sensitive and can determine
a variety of properties associated with glycans, dependent on the ionization mode, number of stages, specific labeling and
enrichment methods. Single stage MS can only reveal oligosaccharide composition but combination of MS with various fragmen-
tation methods have been used for more refined structural determination. Mass spec has traditionally been used with derivatization
methods such as reduction and permethylation of oligosaccharides to facilitate the use of ionization methods such as
collision-induced dissociation in line with tandem mass spectrometry (MS-MS) to determine the primary structure of
oligosaccharides. The past 20 years has seen enormous progress in ionization techniques and methods for glycoproteomic analysis
along with an increase in the database information available and bioinformatics platforms for analysis. In this series, the chapter by
Ni et al., (Chapter 1.13) describes a MS technique called logically derived sequence (LODES) multistage tandem mass spectrometry
(MSn). This technique can determine the primary structure of oligosaccharides, with stereochemical information. The chapters by
Smith (Chapter 1.17), Lauc (Chapter 1.19), and others in Volume 3 also refer to mass spec techniques for glycomics research.
1.01.2.4 NMR spectroscopy and molecular simulations

Nuclear Magnetic Resonance (NMR) spectroscopy is arguably one of the most important and information-rich technique in
chemistry and biochemistry research. When molecules such as glycans, proteins or nucleic acids are placed in a magnetic field,
certain atomic isotopes especially those with a spin quantum number of 1/2, such as 1H, 13C, 15N, 31P and 19F, act like little bar
magnets and align with (or against) the external magnetic field. Application of a radio frequency at the “resonance” energy causes
spins to flip between aligned/unaligned states, and the energy used to cause this is different for atoms in different chemical and
electronic environments (the “chemical shift”). Detection of those states leads to a fingerprint of those atoms in the molecule,
leading to determination of their molecular arrangement. When atoms such as protons and carbons are within 1–5 bonds of one
another, they interact through the electron that make up these bonds and “couple” to each other, causing splits in the energy levels
of their neighbors, leading to more complicated spectra. These coupling constants are different depending on the angle between the
coupling partners, and thus can report on defined arrangements in space. One can see that the information gained from NMR such
as chemical shift and coupling constants leads to assignments of both molecular environment and stereochemistry. In addition,
atoms can “couple” to one another through dipole-dipole interactions through space, and this property, called the nuclear
Overhauser enhancement (NOE), can detect protons that are not coupled through bonds but are close in space. This method
along with through-bond interactions between protons and carbons allows the determination of linkage information between
conjugated monosaccharide units. Reviews of NMR in carbohydrate structure determination are plentiful, and the reader is referred
to these monographs.89–100 A simple NMR spectrum of the disaccharide methyl b-maltoside, taken from Chapter 1.14 by
Widmalm, is shown in Fig. 8.
It is beyond the scope of this chapter to describe NMR theory and practice in detail; suffice it to say, NMR has advanced over the
years to expand to an armamentarium of experiments that include multidimensional NMR that can simultaneously correlate several
NMR-active nuclei that are coupled vicinal, coupled long range or coupled through space. The use of what is known as residual
dipolar couplings has made a tremendous impact on the protein structural biology and that has extended to carbohydrate
structures.93 In addition, many techniques such as Saturation Transfer Difference (STD), WaterLogsy and T2 filtering can detect
these interactions in complexes of carbohydrates and macromolecules (proteins/DNA/RNA).99,101–104 Chapter 3.15 by Jimenez-
Barbero, details the more modern aspects of these techniques.
The composite of all the many sets of information one can glean from NMR can be used to help construct three-dimensional
conformations of glycans. However, from years of structural work on various oligosaccharides, it has been shown that glycosidic
linkages are relatively flexible, and glycans conformations can be highly dynamic. Thus, information obtained by NMR experiments
can be very useful, but insufficient to fully define the conformational space mapped by large oligosaccharides since it reports on
a time-averaged population of conformations. Molecular modeling simulations based on defined force fields that have been curated
by structural information over the course of many decades, can fill this gap.
Molecular mechanics and dynamics are techniques that use what is called a force field to define various atomic and molecular
parameters to closely mimic an actual real-world molecule have evolved dramatically over the years. The availability of structural
data by X-ray crystallography and NMR spectroscopy have fueled the progress to adapt more refined force fields and electronic
Fig. 8 NMR spectrum (left) of methyl b-maltoside (right) with color-coded assignments of the two anomeric protons. HDO is protonated residual solvent from
D2O. The methyl singlet is labeled.
parameters that may yield improved outcomes for defining molecular conformations. Some of the most recognized force field used
in carbohydrate simulations are GAFF1,105,106 CHARMM107–116 and GLYCAM106,117,118 which have been parameterized for the
very unique linkages (anomeric, amino acid-carbohydrate) that are present in oligosaccharides and carbohydrate-protein conju-
gates. Often, NMR data is combined with molecular modeling to “match” each other’s calculations. For example, through-space
interactions defined by NOE’s can be included as “restraints” in simulated structures to maintain specific conformational
adjustments and to insure the fluctuating, calculated conformations do not violate these experimentally-derived limits. An in-depth
discussion of these concepts is available in the chapters by Perez (Chapter 1.15) and Fadda (Chapter 1.16).
1.01.3 Glycan synthesis
The synthesis of glycans of all kinds is of course an entire field to itself. Since the days of Fischer and Hudson, researchers have tried
to synthesize carbohydrate analogs. It was not until perhaps 1953 that the first disaccharide, sucrose, was synthesized by Ray
Lemieux. This was considered a landmark synthesis and his 5% yield was “tops” at the time! Since then, our ability to synthesize
complex glycans has also progressed as other areas of the field. Volume 2 has a full array of chapters to get anyone up to speed on
modern carbohydrate synthesis.
The synthetic routes used to produce oligosaccharides have a few key features that have remained unchanged for generations.
The coupling of two sugar units has commonly been comprised of one saccharide as the glycosyl “donor” and the other the
“acceptor.” The donor will “accept” the second sugar at its anomeric center. Hence the donor needs a leaving group at C1. The
acceptor uses a free hydroxyl as a nucleophile to react with the donor under the auspices of an activating agent that primes the donor
for nucleophilic attack. Since sugars have several free hydroxyl groups, the ones that are not acting as the acceptor nucleophile need
to be masked, or “protected”. After the coupling, a selective deprotection of a separate hydroxyl group frees a second nucleophile to
react with another donor molecule. A schematic of this type of transformation is shown in Fig. 9, taken from Chapter 2.01 by
Oscarson. In the brackets are what are thought to be the intermediate species in the reaction: The top structure is called
an oxocarbenium ion, and through the years, glycosylations were thought to go through this intermediate, making the reaction
an Sn1 like mechanism. There has been some controversy as to the existence of this intermediate and a beautiful discussion of the
theoretical and experimental data can be found in Chapter 2.02 by Blériot.
Glycan synthesis has evolved where there is now an extensive list of functional groups that can be used as donors (thioglycosides,
trichloroacetimidates, xanthates, phosphates, halogens and pentenyl glycosides, to name just a few), an equally large list of
promotors/catalysts and a variety of methods to string together many diverse monosaccharides where reaction economy is
exploited. In addition to chemical synthesis, enzymatic synthesis, through the use of glycosyltransferases and hydrolases, have
made a distinct mark on sugar chemistry in recent years.118 There are several “one-pot” procedures that have been developed that
utilize differential reactivity of donors and acceptors to certain specialized reaction conditions. These were pioneered by
Wong119,120 and have been increasing in popularity. One ingenious method has been developed into an extremely useful technique
in glycan synthesis is the use of a one-pot multi enzyme (OPME) system of Chen.121–124 This system has been expanded to
glycolipids and glycopeptides (Fig. 10).
The one-pot methods were a precursor to the development of automated oligosaccharide synthesis. Prior discussions in this article
confirmed the difficulties in automating glycan assembly. However, great strides have been made in this area since the first edition, and
the chapters by Demchenko (Chapter 2.20), Hurevich (Chapter 2.17) and Downey (Chapter 2.18) outline the latest in this research,
with the development of the first commercial automated oligosaccharide synthesizer, the Glyconeer® (Hurevich Chapter 2.17).
Fig. 9 The glycosylation reaction in schematic form. A donor and an acceptor are coupled through the use of a promotor or catalyst, and a disaccharide is formed,
typically through the intermediacy of the oxocarbenium ion (brackets, top structure).
Fig. 10 OPME strategy: Carbohydrate substrates and starting materials can be chemically modified followed by enzymatic synthesis. The multi-enzyme system
uses enzymes that can recycle the natural nucleotide diphosphate donors. Subsequent modifications may take place and the process repeated.
One mention should be given to the assembly of a sugar from non-sugar precursors, or the de novo synthesis of glycans
(O’Doherty, Chapter 2.14).
1.01.4 Cellular glycan functions
Most reviews on glycans will begin with a paragraph something like this:
“Carbohydrates are the most abundant and structurally diverse naturally occurring organic compounds. They are presented on the surfaces of all types of
cells from different organisms [1]. The cell surface carbohydrate coating (or glycocalyx) can be readily observed under microscopes [2]. Carbohydrates
on mammalian cells are involved in numerous biological and pathological processes including homeostasis, cell-cell interaction, cell migration,
development, bacterial and viral infection, inflammation, immunology, cancer metastasis, etc. [3,4]. The variety of these properties are the results of the
structural diversity of carbohydrates. Unlike proteins and nucleic acids, carbohydrates are not the products of template-driven biosynthesis but are
directly dependent on the expression and substrate specificity of glycosyltransferases as well as the availability of corresponding sugar nucleotides [5].
Diverse monosaccharide building blocks and various stereo- and regiochemistry in glycosidic linkages contribute to the complexity of the linear and
branched structures of carbohydrates. . ...”
The above paragraph recapitulates most of the details of this article: Complexity, multifunctional, non-template biosynthesis,
difficult to isolate or make, etc. The biological functions of glycans are nearly endless, as new roles are discovered often. This series
and other reviews such as the seminal one by Varki13 and his update in 2017 are testaments to how important every variety of
cellular glycan, from bacteria to plants to man are critical for survival. Conversely, they can cause infection and exacerbate illness,
contribute to non-productive cell adhesion and inflammation and drive tumors to be more aggressive and metastasize. As alluded
to above, the first thing any other cell, tissue or molecule “sees” when encountering another cell is a forest of glycans often referred to
as the glycocalyx, and this dense composition of sugars is often involved in orchestration of binding event, permeability of ions and
can be involved in the progression of disease.125–129 This is a collective function of what may be referred to as the “macro” cell
surface glycosylation environment. Each individual glycan may also contribute to structure and function in myriad ways. Recall the
list of glycans that were described in Section 1.01.1.2. Fig. 11 depicts these structures and the wheel lists at least two functions of
each family of glycans. This is simply to set the stage for the fact that all cellular glycans contribute some role in the tertiary structure,
adhesion or biological function of that particular cell type. The importance of this initial meeting between cells is highlighted by
what could be considered the “ultimate” first: We are all aware that life begins by the recognition of eggs by sperm, but it may not be
widely known that this recognition is through a lectin-carbohydrate interaction!130–132
In lieu of attempting any semblance of complete listing of functions for glycans of various forms and from different species, the
reader is referred to the aforementioned reviews and to Volumes 3 and 5 in this series which are dedicated to the biochemistry of
glycans and the role that glycans play in many disease states, respectively. However, a sampling of concepts will be introduced in
Section 1.01.4.2.
1.01.4.1 Glycan binding proteins

While most of this article has been dedicated to the structure of the sugars that are biosynthesized, another group of molecules is
equally important in the function of cellular glycans and these are their binding partners or Glycan Binding Proteins (GBPs).133,134
Fig. 11 Function “wheel” of the most prominent vertebrate glycan types. Inner wheel lists the glycan type and outer wheel lists two of the many functions that
each of the depicted glycans (outside of the wheel) possess.
These make up a huge array of macromolecules that help choreograph the interactions that glycans have with their intrinsic and
extrinsic environs. Most often referred to as lectins, these proteins contain a non-catalytic domain that can reversibly bind to
different carbohydrates, and their specificities can be for glycans from their own or other species. They mediate interactions of
glycans either within their own cellular space, between cells (adhesion) and they may act as a bridge to higher order structures
mediated by the Glycan-Protein interaction. Lectins usually bind their carbohydrate determinants in a shallow groove on the
protein surface, hence the binding affinities for monosaccharides is consequently quite weak; compensation for this weak
interaction is often accomplished by multivalency, the binding of several glycans and proteins simultaneously (cluster glycoside
[“Velcro”] effect).135–137 Chapter 3.16 by Brewer and Dam provides detailed information on the molecular basis of these inter-
actions. Many of these binding events mediate cellular signaling pathways that are essential for cellular survival and/or cell
death.134,138
Much of our knowledge of lectins stems from the proteins that were originally found in plants.139 As far back as the late 19th
century, it was known that some substances from plants could facilitate agglutination of erythrocytes and hence they were termed
hemagglutinins, or phytohemagglutinins since they were derived from plants.140 Work in the 1940s and 1950s by Boyd, Renkonen,
Morgan and Watkins showed that the agglutination properties of these plant molecules were found to be inhibited by certain sugars,
and it was thought that the function of the plant agents was through the binding of carbohydrate moieties on the red blood cells.
This was the beginning and the basis of what would be the work that differentiated various blood types in to their agglutination
properties from plant lectins. Thus the blood group antigens that we know today as A, B, O and AB are defined by carbohydrate
determinants. There are a host of plant lectins that are used as tools in glycobiology in a variety of different ways. A listing of a small
sample of these and their carbohydrate specificities are shown in Table 2.141 Plant lectins have evolved to mediate many essential
roles in the organism, such as their involvement in defense mechanisms, immunity and growth stimulation.142 Since the
recognition of many carbohydrate determinants of plant lectins is transmissible to many types of glycan presentations, these
proteins have been used for decades as tools in early glycomics and glycobiology research, and Chapter 3.18 by Enam some of the
uses of lectins as analytical tools.
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Publisher: Oliver Walter

Ravin Narain, PhD, P.Eng., FRSC is a professor in the Department of Chemical

Naoyuki Taniguchi graduated from the Faculty of Medicine, Hokkaido Univer-

Sébastien Vidal received his PhD in organic chemistry in 2000 (University of

Spencer Williams was born and raised in Albany, Western Australia.

Marya Ahmed Robert S Haltiwanger

Petra Larsen Raja Mazumder

Jayachandran Venkatesan Jeet Kiran Vora

Joseph J. Barchi, Jr.

1.02 Bacterial Exopolysaccharides 21

1.03 Fungal Polysaccharides 96

1.04 Seaweed Polysaccharides: Promising Molecules for Biotechnological Applications 131

1.06 C-Mannosyl Tryptophan: From Chemistry to Cell Biology 163

1.07 O-Fucosylation of Proteins 182

1.08 Structure, Classification and Modification of Polysaccharides 204

1.09 Overview of Cellulose Types and Applications 220

1.10 Mucins: Structure and Function 237

1.11 High-pH Anion-Exchange Chromatography (HPAEC) and Pulsed Amperometric

1.12 Capillary Electrophoresis 290

1.13 Modern Mass Spectrometry Techniques for Oligosaccharide Structure Determination:

1.15 Computational Modeling in Glycoscience 374

1.17 Tools and Methods to Study the Human Glycome 416

1.18 Glycosciences.de: Databases and Tools to Support Research in Glycomics and

1.19 Systems Glycobiology: Immunoglobulin G Glycans as Biomarkers and Functional

1.21 Glycoinformatics Resources Integrated Through the GlySpace Alliance 507

Comprehensive Glycoscience, 2nd edition https://doi.org/10.1016/B978-0-12-819475-1.00108-5 1

1.01.1.1 Brief history of glycoscience

1.01.1.2 What are carbohydrates/glycans and what do they look like?

Scientist (country of origin) Notable Discovery Year

Fig. 6 Sampling of some unusual saccharides found in various species of bacteria.

Fig. 7 Analogs of sialic acid found in various species of bacteria.

1.01.2 Analysis of glycans

1.01.2.2 Capillary electrophoresis (CE)

1.01.2.3 Mass spectrometry

1.01.2.4 NMR spectroscopy and molecular simulations

1.01.3 Glycan synthesis

1.01.4 Cellular glycan functions

1.01.4.1 Glycan binding proteins

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