Transforming Glycoscience A Roadmap for the Future (2012) / Chapter Skim
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4 Examples of Outstanding Questions in Glycoscience
4 Examples of Outstanding Questions in Glycoscience
Pages 71-84
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From page 71... ...
is underdeveloped are many, but they largely come down to four factors: the astonishing complexity of glycan structures and biochemistry dwarfs the complexity of both nucleic acids and proteins; the relative lack of tools to probe and understand glycan structure and biochemistry in light of that complexity; the lack of adequate data resources and informatics tools for their analysis; and the lack of education in glycoscience. Today, glycoscience sits at a crossroads.
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From page 72... ...
Glycans on host cells may be targets for pathogen recognition, and glycans can undergo subtle changes that may allow evasion from a pathogen, even while preserving sufficient intrinsic function. Glycans appear to remain a preferred class of molecules for the cell surface given their tolerance of such subtle changes, while proteins appear to be somewhat less tolerant of sequence changes, which more frequently result in loss of structure or function.
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From page 73... ...
The structural diversity of glycans arises from the various linkage combinations between the monosaccharides that make up glycans, and those linkages are determined by an array of more than 250 enzymes in the human secretory pathway that support glycan synthesis and processing, including a suite of glycosyltransferases that add sugars using activated sugar donors and glycosidases that cleave them (Ohtsubo and Marth 2006; Varki 2006)
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From page 74... ...
A central hypothesis of glycobiology is that cellular control over glycoprotein microheterogeneity allows for precise regulation and diversification of function, not unlike the manner in which splice variants of a transcript impart greater flexibility to gene function. However, unlike the characterization of splice diversity, the experimental techniques that would allow assignment of specific functions to identified glycans on individual proteins are still in their infancy.
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From page 75... ...
4.4 WHAT ARE THE THREE-DIMENSIONAL STRUCTURES OF INTACT GLYCOPROTEINS? The majority of proteins in mammals are glycosylated, and carbohydrate components play essential roles in development, in the immune response, in intercellular communications that may be defective (e.g., in cancer cells)
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From page 76... ...
O-GlcNAc glycosylation is nearly as abundant as protein phosphorylation, and the two have extensive cross talk between them to regulate signaling and transcription in response to nutrients and stress. O-GlcNAc also modifies cytoskeleton proteins and the contractile machinery in cells and muscles.
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From page 77... ...
In other cases the recognition of a defined structure on a cell surface can vary enormously depending on the nature of the other glycans on the same cell surface. For example, three different glycan-binding proteins that recognize -26-linked sialic acids and display identical binding patterns on glycan arrays show remarkably different patterns when binding to the surface of red blood cells.
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From page 78... ...
recognition of host (animal, plant) glycans, host recognition of microbial glycans, molecular mimicry of host glycans by pathogens, and microbial community interactions involving glycans.
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From page 79... ...
For example, mammalian GBPs mediate diverse biology, including trafficking of white blood cells to sites of inflammation, regulation of cell-signaling receptors, and aiding the immune system to distinguishing between self and nonself. Plant GBPs mediate defense against pathogens while also facilitating critical symbiotic relationships with bacteria required for essential processes, such as nitrogen fixation.
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From page 80... ...
Similarly, although analytical methods exist to profile glycans of complex biological systems, these methods provide limited information, and methods to routinely determine the complete structures of glycans from biological materials are lacking. Also needed are glycan reagents to probe the functions of GBP-ligand interactions and to produce glycan-specific antibodies.
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From page 81... ...
4.11 HOW CAN SUGARS BE REASSEMBLED TO DEVELOP MATERIALS WITH TAILORED PROPERTIES AND FUNCTIONALITY? The ability to reassemble sugar units on demand to make new polymer structures will provide limitless opportunities to design materials that have tailored properties or that are functionality specific for a given application.
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From page 82... ...
Improvements in polysaccharide isolation procedures to produce homogenous samples, in characterization methods that have increased structural sensitivity and speed, and in predictive modeling to give additional insight into synthesis pathways and properties of the resulting materials, will be important as well. 4.12SUMMARY The questions posed in this chapter address several overarching themes, many of which reflect gaps in knowledge about fundamental biological and biochemical processes:
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From page 83... ...
Although these areas address fundamental aspects of glycans, they also form a base from which to apply glycoscience knowledge to solve practical problems, such as how to better diagnose and treat diseases, how to create new fuels, and how to design improved products. Addressing the questions posed in this chapter has relevance to glycoscientists and nonglycoscientists alike.
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