ESSENTIALS OF GLYCOBIOLOGY 2ND EDITION PDF

Diagrammatic representation of the five distinct types of sugar-peptide bonds that more A glycophosphatidylinositol anchor is a glycan bridge between phosphatidylinositol and a phosphoethanolamine that is in amide linkage to the carboxyl terminus of a protein. This structure typically constitutes the only anchor to the lipid bilayer membrane for such proteins see Chapter A glycosphingolipid often called a glycolipid consists of a glycan usually attached via glucose or galactose to the terminal primary hydroxyl group of the lipid moiety ceramide , which is composed of a long chain base sphingosine and a fatty acid see Chapter

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Diagrammatic representation of the five distinct types of sugar-peptide bonds that more A glycophosphatidylinositol anchor is a glycan bridge between phosphatidylinositol and a phosphoethanolamine that is in amide linkage to the carboxyl terminus of a protein. This structure typically constitutes the only anchor to the lipid bilayer membrane for such proteins see Chapter A glycosphingolipid often called a glycolipid consists of a glycan usually attached via glucose or galactose to the terminal primary hydroxyl group of the lipid moiety ceramide , which is composed of a long chain base sphingosine and a fatty acid see Chapter Glycolipids can be neutral or anionic.

A ganglioside is an anionic glycolipid containing one or more residues of sialic acid. It should be noted that these represent only the most common classes of glycans reported in eukaryotic cells.

There are several other less common types found on one or the other side of the cell membrane in animal cells see Chapters 12 and Although different glycan classes have unique core regions by which they are distinguished, certain outer structural sequences are often shared among different classes of glycans. In contrast, glycosaminoglycans are linear copolymers of acidic disaccharide repeating units, each containing a hexosamine GlcN or GalN and a hexose Gal or hexuronic acid GlcA or IdoA see Chapter Keratan sulfate is actually a 6-O-sulfated form of poly-N-acetyllactosamine attached to an N- or O-glycan core, rather than to a typical Xyl-Ser-containing proteoglycan linkage region.

The glycosaminoglycans except for hyaluronan also typically have sulfate esters substituting either amino or hydroyxl groups i. Another anionic polysaccharide that can be extended from LacNAc units is polysialic acid , a homopolymer of sialic acid that is selectively expressed only on a few proteins in vertebrates.

Polysialic acids are also found as the capsular polysaccharides of certain pathogenic bacteria Chapter A few percent of known genes in the human genome are dedicated to producing the enzymes and transporters responsible for the biosynthesis and assembly of glycan chains see Chapter 7 , typically as posttranslational modifications of proteins or by glycosylation of core lipids. Thus, even with full knowledge of the expression levels of all relevant gene products, we do not understand enough about the structures and pathways to predict the precise structures of glycans elaborated by a given cell type.

Furthermore, small changes in environmental cues can cause dramatic changes in glycans produced by a given cell. It is this variable and dynamic nature of glycosylation that makes it a powerful way to generate biological diversity and complexity.

Of course, it also makes glycans more difficult to study than nucleic acids and proteins. This term indicates that at any given glycan attachment site on a given protein synthesized by a particular cell type, a range of variations can be found in the structures of the attached glycan chain. The extent of this microheterogeneity can vary considerably from one glycosylation site to another, from glycoprotein to glycoprotein, and from cell type to cell type.

Mechanistically, microheterogeneity might be explained by the rapidity with which multiple, sequential, partially competitive glycosylation and deglycosylation reactions must take place in the endoplasmic reticulum ER and Golgi apparatus, through which a newly synthesized glycoprotein passes see Chapter 3. An alternate possibility is that each individual cell or cell type is in fact exquisitely specific in the details of the glycosylation that it produces, but that intercellular variations result in the observed microheterogeneity of samples from natural multicellular sources.

From a functional point of view, the biological significance of microheterogeneity remains unclear. Thus, for example, newly synthesized proteins originating from the ER are either cotranslationally or posttranslationally modified with sugar chains at various stages in their itinerary toward their final destinations.

The glycosylation reactions usually use activated forms of monosaccharides nucleotide sugars ; see Chapter 4 as donors for reactions that are catalyzed by glycosyltransferases for details about their biochemistry, molecular genetics, and cell biology, see Chapters 3 , 5 , and 7. In almost all cases, these nucleotide donors are synthesized within the cytosolic or nuclear compartment from monosaccharide precursors of endogenous or exogenous origin see Chapter 4.

To be available to perform the glycosylation reactions, the donors must be actively transported across a membrane bilayer into the lumen of the ER and Golgi compartments. Much effort has gone into understanding the mechanisms of glycosylation within the ER and the Golgi apparatus, and it is clear that a variety of factors determine the final outcome of glycosylation reactions.

Some bulky sugar chains are made on the cytoplasmic face of these intracellular organelles and are flipped across their membranes to the other side, but most are synthesized by adding one monosaccharide at a time to the growing glycan chain on the inside of the ER or the Golgi. Regardless, the portion of a glycoconjugate that faces the inside of these compartments will ultimately face the inside of a secretory granule or lysosome and will be topologically unexposed to the cytosol.

The biosynthetic enzymes glycosyltransferases, sulfotransferases, etc. A classical model envisioned that these enzymes are physically lined up along this pathway in the precise sequence in which they actually work. This appears to be an oversimplified view, because there is considerable overlap in the distribution of these enzymes, and the actual distribution of a given enzyme seems to depend on the cell type. All of the topological considerations mentioned above are reversed with regard to nuclear and cytoplasmic glycosylation , because the active sites of the relevant glycosyltransferases face the cytosol, which is in direct communication with the interior of the nucleus.

Until the mids, the accepted dogma was that glycoconjugates, such as glycoproteins and glycolipids, occurred exclusively on the outer surface of cells, on the internal luminal surface of intracellular organelles, and on secreted molecules.

As discussed above, this was consistent with knowledge of the topology of the biosynthesis of the classes of glycans known at the time, which took place within the lumen of the ER-Golgi pathway. Thus, despite some clues to the contrary, the cytosol and nucleus were assumed to be devoid of glycosylation capacity. However, it is now clear that certain distinct types of glycoconjugates are synthesized and reside within the cytosol and nucleus see Chapter Indeed, one of them, called O-linked GlcNAc see Chapter 18 , may well be numerically the most common type of glycoconjugate in many cell types.

The fact that this major form of glycosylation was missed by so many investigators for so long serves to emphasize the relatively unexplored state of the whole field of glycobiology. Like all components of living cells, glycans are constantly being degraded and the enzymes that catalyze this process cleave sugar chains either at the outer nonreducing terminal end exoglycosidases or internally endoglycosidases see Chapters 3 and Some terminal monosaccharide units such as sialic acids are sometimes removed and new units reattached during endosomal recycling, without degradation of the underlying chain.

The final complete degradation of most glycans is generally performed by multiple glycosidases in the lysosome. Once broken down, their individual unit monosaccharides are then typically exported from the lysosome into the cytosol so that they can be reused see Figure 1. In contrast to the relatively slow turnover of glycans derived from the ER-Golgi pathway, the O-GlcNAc monosaccharide modifications of the nucleus and cytoplasm may be more dynamic and rapidly turned over see Chapter Biosynthesis, use, and turnover of a common monosaccharide.

This schematic shows the biosynthesis, fate, and turnover of galactose, a common monosaccharide constituent of animal glycans. Although small amounts of galactose can be taken up from the outside more Even when they are found as linear macromolecules e. Thus, the complete sequencing of glycans is practically impossible to accomplish by a single method and requires iterative combinations of physical, chemical, and enzymatic approaches that together yield the details of the structure under study for a discussion of the various forms of low- and high-resolution separation and analysis, including mass spectrometry and NMR, see Chapter Less detailed information on structure may be sufficient to explore the biology of some glycans and can be obtained by simple techniques, such as the use of enzymes endoglycosidases and exoglycosidases , lectins, and other glycan-binding proteins see Chapters 45 and 47 , chemical modification or cleavage, metabolic radioactive labeling, antibodies, or cloned glycosyltransferases Chapter Glycosylation can also be perturbed in a variety of ways, for example, by glycosylation inhibitors and primers Chapter 50 and by genetic manipulation of glycosylation in intact cells and organisms Chapter The directed in vitro synthesis of glycans by chemical and enzymatic methods has also taken great strides in recent years, providing many new tools for exploring glycobiology Chapters 49 and The generation of complex glycan libraries by a variety of routes has further enhanced this interface of chemistry and biology Chapter In reality, the glycome is far more complex than the genome or proteome.

In addition to the vastly greater structural diversity in glycans, one is faced with the complexities of glycosylation microheterogeneity see above and the dynamic changes that occur in the course of development, differentiation, metabolic changes, malignancy, inflammation, or infection.

Added diversity arises from intraspecies and interspecies variations in glycosylation. Thus, a given cell type in a given species can manifest a large number of possible glycome states. Glycomic analysis today generally consists of extracting entire cell types, organs, or organisms; releasing all the glycan chains from their linkages; and cataloging them via approaches such as mass spectrometry. In a variation called glycoproteomics , the glycans are analyzed while still attached to protease-generated fragments of glycoproteins.

The results obtained represent a spectacular improvement over what was possible a few decades ago, but they still constitute an effort analogous to cutting down all the trees in a forest and cataloging them, without attention to the layout of the forest and the landscape. This type of glycomic analysis needs to be complemented by classical methods such as tissue-section staining or flow cytometry, using lectins or glycan-specific antibodies that aid in understanding the glycome by taking into account the heterogeneity of glycosylation at the level of the different cell types and subcellular domains in the tissue under study.

This is even more important because of the common observation that removing cells from their normal milieu and placing them into tissue culture can result in major changes in the glycosylation machinery of the cell. However, such classical approaches suffer from poor quantitation and relative insensitivity to structural details.

A combination of the two approaches is now potentially feasible via laser-capture microdissection of specific cell types directly from tissue sections, with the resulting samples being studied by mass spectrometry. Because most of the genes involved in glycan biosynthetic pathways have been cloned from multiple organisms, it is possible today to obtain an indirect genomic and transcriptomic view of the glycome in a specific cell type see Chapter 7.

However, given the relatively poor correlation between mRNA and protein levels, and the complex assembly line and competitive nature of the cellular Golgi glycosylation pathways, even complete knowledge of the mRNA expression patterns of all relevant genes in a given cell cannot allow accurate prediction of the distribution and structures of glycans in that cell type. In other words, there is as yet no reliable indirect route toward elucidating the glycome, other than by actual structural analysis using an array of methods.

Indeed, with few exceptions, mutants with specific defects at most steps of the major pathways of glycan biosynthesis have been found in cultured animal cells. The use of such cell lines has been of great value in elucidating the details of glycan biosynthetic pathways. Their existence implies that many types of glycans are not crucial to the optimal growth of single cells living in the sheltered and relatively unchanging environment of the culture dish.

In keeping with this supposition, genetic defects completely eliminating major glycan classes in intact animals all cause embryonic lethality see Chapter 42 and Table 6. As might be expected, naturally occurring viable animal mutants of this type tend to have disease phenotypes of intermediate severity and show complex phenotypes involving multiple systems. Less severe genetic alterations of outer chain components of glycans tend to give viable organisms with more specific phenotypes see Chapter 42 and Table 6.

Overall, there is much to be learned by studying the consequences of natural or induced genetic defects in intact multicellular organisms see Chapter Like any biological system, the optimal approach carefully considers the relationship of structure and biosynthesis to function see Chapter 6. As might be imagined from their ubiquitous and complex nature, the biological roles of glycans are quite varied. Indeed, asking what these roles are is akin to asking the same question about proteins.

Thus, all of the proposed theories regarding glycan function turn out to be partly correct, and exceptions to each can also be found. Not surprisingly for such a diverse group of molecules, the biological roles of glycans span the spectrum from those that are subtle to those that are crucial for the development, growth, function, or survival of an organism for further discussion, see Chapter 6.

The diverse functions ascribed to glycans can be more simply divided into two general categories: i structural and modulatory functions involving the glycans themselves or their modulation of the molecules to which they are attached and ii specific recognition of glycans by glycan-binding proteins.

Of course, any given glycan can mediate one or both types of functions. The binding proteins in turn fall into two broad groups: lectins and sulfated GAG-binding proteins see Chapter Such molecules can be either intrinsic to the organism that synthesized the cognate glycans e. The atomic details of these glycan-protein interactions have been elucidated in many instances see Chapter Although there are exceptions to this notion, the following general theme has emerged regarding lectins: Monovalent binding tends to be of relatively low affinity, although there are exceptions to this notion, and such systems typically achieve their specificity and function by achieving high avidity, via interactions of multivalent arrays of glycans with cognate lectin -binding sites see Chapters 30 and Certain relatively specific changes in expression of glycans are also often found in the course of transformation and progression to malignancy see Chapter 44 , as well as other pathological situations such as inflammation.

These spatially and temporally controlled patterns of glycan expression imply the involvement of glycans in many normal and pathological processes, the precise mechanisms of which are understood in only a few cases. There are clearly shared and unique features of glycosylation in different kingdoms and taxa. Intraspecies and interspecies variations in glycosylation are also relatively common.

It has been suggested that the more specific biological roles of glycans are often mediated by uncommon structures, unusual presentations of common structures, or further modifications of the commonly occurring saccharides themselves.

Such unusual structures likely result from such unique expression patterns of the relevant glycosyltransferases or other glycan -modifying enzymes. On the other hand, such uncommon glycans can be targets for specific recognition by infectious microorganisms and various toxins. Thus, at least a portion of the diversity in glycan expression in nature must be related to the evolutionary selection pressures generated by interspecies interactions e.

In other words, the two different classes of glycan recognition mentioned above mediated by intrinsic and extrinsic glycan-binding proteins are in constant competition with each other, with regard to a particular glycan target. The specialized glycans expressed by parasites and microbes that are of great interest from the biomedical point of view see Chapters 20 , 21 , and 40 are themselves presumably subject to evolutionary selection pressures. The evolutionary issues presented above are further considered in Chapter 19 , which also discusses the limited information concerning how various glycan biosynthetic pathways appear to have evolved and diverged in different life forms.

For example, heparin , a sulfated glycosaminoglycan, and its derivatives are among the most commonly used drugs in the world.

CHORITROHIN PDF

Essentials of glycobiology

Bulk discounts available for your lab or class. Click here to inquire. Click here for more information. Description Description In multicellular organisms, cell death is required for normal development, homeostasis, and the elimination of infected or injured cells. The mechanisms by which cell death occurs are genetically encoded and carefully controlled. Perturbations that enhance or suppress cell death may lead to cancer, neurodegeneration, and inflammatory diseases.

LA CATEDRAL BARRIOS TAB PDF

The expanding world of glycobiology

The field has developed a unique identity from its parent disciplines—molecular and cellular biology—because the study of carbohydrates has lagged behind that of nucleic acids and proteins. This is due in part to the lack of tools to probe this class of biomolecules, although recent progress is beginning to correct this deficiency. Given the rapid pace of research in glycobiology, the second edition of Essentials of Glycobiology, published early this year, is more than welcome. This new edition is doubly welcome as it continues the experiment of publishing the full book simultaneously in print and online—easily accessible by a title search on the US National Institutes of Health website. This book, although written as a textbook for a graduate-level course in glycobiology, serves as a great introduction to this exciting area for the general reader with an undergraduate background in organic chemistry and biology. The book relies on a group of editors and experts for its exposition and fortunately still coheres nicely as a complete work.

FOLICULITIS QUELOIDE DE LA NUCA PDF

Essentials of Glycobiology

Red arrows illustrate the path to follow along the sugar backbone when correlating the stereochemistry of the Fischer projection with the chair conformation. At present, the more structurally accurate chair representations are preferred to Haworth projections for depicting pyranoses. However, Haworth projections are still commonly used for depicting furanoses. The furanose ring is rather flexible and not entirely flat in any of its energetically favored conformations; for example, it has a slight pucker when viewed from the side, as seen in the representations of the so-called envelope and twist or skew conformations Figure 2. Because furanoses can adopt many low-energy conformations, researchers have adopted the Haworth projection as a simple means to avoid this complexity. The new asymmetric center is termed the anomeric carbon i. Two stereoisomers are formed by the cyclization reaction because the anomeric hydroxy group can assume two possible orientations.

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