Transforming Glycoscience A Roadmap for the Future (2012) / Chapter Skim
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3 Glycoscience in Health, Energy, and Materials
3 Glycoscience in Health, Energy, and Materials
Pages 37-70
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From page 37... ...
They also help illustrate how glycoscience knowledge will be embedded in efforts to address fundamental challenges in health and sustainability. The chapter begins with examples and questions related to human health because this has been a major focus of efforts in the field of glycoscience and glycomics, particularly in the United States.
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From page 38... ...
. The signaling associated with these molecular patterns is part of the multistep process that results in leukocyte homing into affected tissues, a process initiated when leukocytes adhere to activated endothelial cells lining blood vessel walls.
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From page 39... ...
Figure 3-1 able to bind tightly to glycoprotein receptors, called integrins, which can Bitmapped lead to penetration of the endothelial cell monolayer and its basement membrane. The mechanisms for the initial binding and rolling of leukocytes have been studied extensively and involve transient expression of highly regulated glycan-binding proteins, called selectins, that decorate the surfaces of leukocytes, activated platelets, and activated endothelial cells.
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From page 40... ...
for antibody binding and the generation of immune responses. The general importance of glycans in immunity has been appreciated for many years, and the early discovery that the ABO blood groups derive from specific glycan structures is just one example (Morgan and Watkins 1969)
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From page 41... ...
. Meanwhile, host glycans such as sialic acids serve as self-associated molecular patterns.
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From page 42... ...
There are currently 17 known siglecs encoded in primate genomes, each with a different immune cell type distribution and function. The types of sialyl-oligosaccharides and the structures of the sialic acids on the surfaces of immune cells also play key roles in the activity of siglec regulation of immune cell functions.
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From page 43... ...
. The variety of different glycan structures in human milk is enormous, and recently developed glycomic methods are beginning to elucidate the human milk glycome (Chichlowski et al.
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From page 44... ...
Avian viruses recognize 2-3 linked sialic acids found in susceptible cells in birds, while human influenza viruses recognize 2-6 linked sialic acids, which are found in human airway cells (Stevens et al. 2006; Viswanathan et al.
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From page 45... ...
. However, recent findings show that humans immune to HIV produce antibodies that bind to the glycan shield and neutralize infection by most HIV strains (McLellan at al.
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From page 46... ...
Given the success of glycan-based vaccines against bacteria and the growing knowledge with respect to novel lineage-specific glycans in parasites, this area also represents a promising target for future vaccine development While only a few examples are given here, it is clear that glycans play a central role in our battle against invading organisms of all types. As antibiotic resistance continues to rise, and the need for antivirals and antiparasitics becomes acute, more focused efforts to understand the central roles of glycans in infectious disease and vaccine development will be increasingly important.
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From page 47... ...
. Both the glycocalyx of endothelial cells and the modification of contractile machinery and transcription factors regulating the expression of key cardiac proteins represent novel targets for therapeutic discovery.
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From page 48... ...
. Research has shown that elevated free fatty acids or a high-fat diet cause nuclear exclusion and loss of expression of key transcription factors regulating the expression of a glycosyltransferase, called GnT-4a, in the beta cells of the pancreas (Ohtsubo et al.
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From page 49... ...
In addition, recent advances in glycan synthetic chemistry and chemical biology, as well as the development of novel analytical tools, have produced a convergence of proteomics and glycomics to develop improved biomarkers in this area (Drake et al.
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From page 50... ...
The glycocalyx of tumor cells plays a key role in masking surface antigens and evading immune surveillance mechanisms. While it is clear that cell surface glycans and glycan-binding proteins contribute to all stages of cancer progression and metastasis, and thus may provide novel targets for therapy, there is still much to be learned about the specific roles of glycans in cancer.
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From page 51... ...
3.1.7 Critical Roles of Glycans in Human Development Genetic diseases of both glycan biosynthesis and glycan degradation clearly establish the critical roles of glycans in human development. Currently, there are some 4,500 identified genetic disorders, with the biochemical cause unknown for 2,700.
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From page 52... ...
Many glycan storage diseases involve proteoglycan or glycosaminoglycan accumulation (Coutinho et al.
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It has been estimated that as few as 20 thousand glycan structures might represent most of the binding specificities of known human glycanbinding proteins (Cummings 2009; Smith et al.
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From page 54... ...
However, only recently have they realized the importance of understanding the types of glycans attached to antibodies, which play roles in their efficacy and safety. For example, antibodies made in cultured cells or animals often have glycan structures attached to them that differ from those made by humans, and these changes can elicit deleterious immune responses and affect therapeutic effectiveness.
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From page 55... ...
A major underlying theme for the development of biomass resources is the role of sugars in the formation of the complex glycans that make up the bulk of plant cell walls. In principle, these complex glycans, if processed efficiently, can serve as a renewable source of high-value biofuels and bioproducts in much the same way that oil serves as the source of high-value fuels and petroleum products.
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From page 56... ...
. 3.2.1 Biomass -- Plant Cell Walls Plant cells walls represent Earth's dominant biological carbon sequestration system.
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From page 57... ...
2010, used with permission. Figure 3-3 Bitmapped yet to be clarified is the role that Golgi-localized NDP-sugar transporters play in the subsequent synthesis of polysaccharides and the identity of all of the glycan syntheses and glycosyltransferases involved in the production of the component polymers of plant cell walls (Bar-Peled and O'Neill 2011)
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From page 58... ...
It also arises from the plant's need to evolve resistance to attack by the elements and from microbes and their enzymes. There are several approaches to overcoming this recalcitrance, including: · creation of a modified cell wall architecture that would be more susceptible to deconstruction by microbes or enzymes, · reduction of the inhibitors in plant cell walls that reduce the effi ciency of microbial and enzymatic deconstruction, · reduction or modification of the cell wall lignin content, and · increase in the amorphous cellulose and hemicellulose content of the cell wall and increase in susceptibility to breakdown.
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From page 59... ...
Efforts are under way to develop improved enzymes and other catalysts for decomposing cell walls, and an understanding of plant recalcitrance helps in both the design of new molecules and investigating how and why different cell walls respond differently to them (Himmel et al. 2007; Rubin 2008; Carroll and Somerville 2009; Van de Vyver et al.
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From page 60... ...
Addressing this challenge will require continued research into the cell wall formation and breakdown process and forms an important part of the glycoscience field. As a result, the committee finds that: · Plant cell walls, made mostly of glycans, represent the planet's dominant source of biological carbon sequestration, or biomass, and are a potentially sustainable and economical source of non petroleum-based energy.
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From page 61... ...
In other words, it takes plants three days to produce biomass in the form of cell walls equal to the total annual output of the world's chemical industry (DOE 2011)
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From page 62... ...
This vision can be achieved by providing mechanisms to develop an increased understanding of polysaccharide biosynthesis in plants and trees, new characterization tools and methods for understanding polysaccharide structure, new methods for polysaccharide isolation, synthetic process and chemical modification, and improved predictive modeling capabilities. 3.3.1 Fine Chemicals and Feedstocks A variety of polysaccharides are being investigated in the production of functional chemical precursors that are then subsequently used to make industrially relevant chemicals and engineering polymers (Bozell and Petersen 2010)
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From page 63... ...
Such materials have the potential for new applications in flexible electronics and displays. Cellulose, in this case derived from bacteria, can also be used to make thin, flexible tubes for use as implanted blood vessels.
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From page 64... ...
Research has also yielded reaction pathways that create cellulose derivatives such as cellulose acetate, cellulose acetate propionate, cellulose acetate butyrates, carboxymethyl cellulose, cellulose butyrate succinate, and cellulose acetate propionate (Klemm et al.
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From page 65... ...
. CNs can have either a rod and whiskerlike structure or a fibril particle morphology, with the dimensions varying depending on cellulose source, extraction methods, and extraction conditions (Habibi et al.
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From page 66... ...
Bottom, Transmission electron Figure 3-4 micrograph of cellulose nanocrystals produced by acid hydrolysis.
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From page 67... ...
This vision can be achieved with advances in the following areas, each of which are described in the sections that follow: · understanding cellulose nanomaterial extraction processes, · CN characterization, · atomistic modeling of cellulose, and · cellulose synthesis. 3.3.3.1 Understanding cellulose nanomaterial extraction processes Unlike the extractions generally needed to produce fine chemicals, feedstocks, and new polymers, the techniques needed to extract completely ordered polysaccharide particles from natural cellulose source materials demand particular delicacy, and developing suitable processing technologies requires new techniques and methodologies.
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From page 68... ...
In addition, improved characterization of structure, nanomechanical properties, and surface chemistry will provide the opportunity to better understand processing-structureproperty relationships as they relate to the CN particles themselves and to CN-CN and CN-water interactions, all of which are important for the design of composite materials with improved performance. While the cellulose polymorph structures of CNs are generally known, characterization of individual CNs is currently lacking in such areas as the percentage of crystallinity, the location of amorphous regions on the CN surface or throughout the CN core, the fraction of a given cellulose polymorph structure and its location in the particle, the identification of defects such as missing cellulose chains, and the hydrogen bonding networks both within and between cellulose chains in the CN.
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From page 69... ...
3.3.3.4 Cellulose synthesis Today, it is particularly challenging to synthesize ordered polysaccharides with the desired surface chemistry that self-assembles with controlled crystalline properties. Through detailed understanding of the polysaccharide biosynthesis process, it will ultimately be possible to develop processing routes that facilitate tailoring both the side-group chemistries of the polysaccharide backbone structure and the assembly of individual chains into an ordered chain structure.
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From page 70... ...
As a result, the committee finds that: · By fostering a greater understanding of the properties of gly cans and of plant cell wall construction and deconstruction, glycoscience can play an important role in the development of nonpetroleum-based sustainable new materials. · Glycan-based materials have wide-ranging uses in such areas as fine chemicals and feedstocks, polymeric materials, and nanomaterials.
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