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ScienceWeek
BIOCHEMISTRY: GLYCOBIOLOGY
The following points are made by R. Sasisekharan and J.R. Myette (American Scientist 2003 91:432):
1) Carbohydrates are indispensable to life on Earth. In their simplest form, they serve as a primary energy source for sustaining life. For the most part, however, carbohydrates exist not as simple sugars but as complex molecular conjugates, or glycans. Glycans come in many shapes and sizes, from linear chains (polysaccharides) to highly branched molecules bristling with antennae-like arms. And although proteins and nucleic acids such as DNA have traditionally attracted far more scientific attention, glycans are also key to life. They are ubiquitous in nature, forming the intricate sugar coat that surrounds the cells of virtually every organism and occupying the spaces between these cells. As part of this so-called extracellular matrix, glycans, with their diverse chemical structures, play a crucial role in transmitting important biochemical signals into and between cells. In this way, these sugars guide the cellular communication that is essential for normal cell and tissue development and physiological function.
2) In recent years, researchers have studied a class of linear glycans known as glycosaminoglycans (or GAGs for short), and particularly a subset known as HSGAGs, which are made up of heparan sulfate and its relative heparin. Biologists are beginning to understand and appreciate the integral roles these glycans play in numerous biological processes relevant to health and disease. HSGAGs are structurally diverse and differ in their chemical composition, especially with regard to the number and position of sulfate groups and the biological form in which they exist. The highly sulfated heparin is produced by connective tissue mast cells. Heparan sulfate, which has more variation in its sulfate groups, is made by practically all animal cells.
3) Recent technical advances have shed a good deal of light on the fine structure of HSGAGs as well as on their functions. The growing ability to determine the structure and biological context of glycans is throwing open the field of glycobiology, leading to a broader understanding of the crucial roles that these glycans play in normal physiology and in disease processes ranging from cancer to microbial infection. This new understanding opens the door to novel carbohydrate-based drug therapies.
4) An HSGAG chain may be generically described as a linear repeat of approximately 10 to 100 disaccharide building blocks that, when linked together, make up the backbone of each sugar molecule. In its most fundamental form, each disaccharide unit consists of two chemically distinct monosaccharides (a uronic acid and a glucosamine) linked by a glycosidic bond. The chains can vary a great deal in their structural configuration because the disaccharide building blocks may be chemically modified at a number of positions. These modifica-tions include the removal of the two-carbon acetyl groups at the amino position of the glucosamine portion and the addition of sulfate groups at several different positions, along with distinctions in the stereochemical arrangement of bonds around specific carbons.
American Scientist http://www.americanscientist.org
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ON CHEMICAL GLYCOBIOLOGY
Carbohydrates are the most abundant organic molecules in nature, with a wide range of functions that include providing a significant fraction of the energy in the diet of most organisms, a storage form of energy in the body, and serving as cell membrane components that mediate certain forms of intercellular communication. Carbohydrates also serve as structural components of many organisms, including the cell walls of bacteria, the exoskeleton of many insects, and the fibrous cellulose of plants. The empiric formula for many of the simpler carbohydrates is [CH(sub2)O](subn), thus the historical name "hydrate of carbon". The name, however, is a misnomer --carbohydrates are not hydrates of carbon.
The term "saccharide" refers to any carbohydrate, especially to simple sugars. Of saccharides there are 4 general classes: monosaccharides, disaccharides, oligosaccharides, and polysaccharides (also called "glycans"), with all cases except monosaccharides consisting of a simple sugars in a chain of glycosidic linkages.
The term "oligosaccharides" usually refers to carbohydrates involving 2 to 20 sugars in a chain, although some authors use "polysaccharide" for any carbohydrate chain involving more than 10 sugars.
In this context, the term "protein prosthetic group" refers in general to any specific non-protein component combined with a protein in stoichiometric proportion, the components usually essential for some special biological function such as catalytic activity of an enzyme. Also in this context, the term "antigen" refers to any chemical moiety that provokes an immune response.
The term "glycoproteins" refers in general to proteins to which oligosaccharides are attached. The glycoprotein carbohydrate chains are often branched rather than linear, and they may or may not be negatively charged. In general, depending on type, glycoproteins contain highly variable amounts of carbohydrate. Membrane-bound glycoproteins participate in a broad range of cellular phenomena, including cell-surface recognition (by other cells, by hormones, and by viruses), cell-surface antigenicity (e.g., blood group antigens), as components of the *extracellular matrix, and as components of various biological "lubricants" (mucins) of the gastrointestinal and urogenital tracts. In addition, almost all the globular proteins present in human plasma (with the notable exception of albumin), and the secreted enzymes and proteins, are glycoproteins.
In general, the term "glycolipids" refers to compounds in which fatty acids are attached to sugars. Glycolipids are essential components of all membranes in the body, but they are found in greatest amounts in nerve tissue, primarily in the outer layer of the plasma membrane, where they interact with the extracellular environment. Glycolipids play a role in the regulation of cellular interactions, growth, and development. Glycolipids are usually very antigenic, and they have been identified as a source of blood group antigens, various embryonic antigens specific for particular stages of fetal development, and as a source of tumor antigens. Glycolipids also serve as cell surface receptors for cholera and diphtheria toxins, as well as for certain viruses. In general, when cells are transformed into cancer cells, there is a dramatic change in the glycolipid composition of the cell membrane. Genetic disorders resulting in the intracellular accumulation of glycolipids lead to serious impairment of the nervous system and impairment of fetal development. Glycoproteins and glycolipids are considered together as "glycoconjugates".
The term "endoplasmic reticulum" refers to an intracellular irregular network of membranes visible only by electron microscopy, the network occurring in many *eukaryotic cells. The membranes form a complex meshwork of tubular channels that are often expanded into cavities ("cisterns"). There are two forms of endoplasmic reticulum: a) the rough (granular) form, with *ribosomes adhering to the outer surface; b) the smooth form, with no ribosomes attached. The functions of the two forms of endoplasmic reticulum differ: the ribosomes of the rough endoplasmic reticulum are the sites of protein synthesis, while the smooth endoplasmic reticulum receives proteins synthesized by ribosomes and is involved in the synthesis of various important lipids.
The term "Golgi apparatus" refers to a compound membranous cytoplasmic organelle of eukaryotic cells, the system consisting of flattened ribosome-free vesicles arranged in a more or less regular stack. In general, the Golgi apparatus processes proteins produced by the ribosomes of the rough endoplasmic reticulum, such processing including modification of the oligosaccharides of glycoproteins, and the sorting and packaging of proteins for transport to a variety of cellular locations. The Golgi apparatus is also a major site of synthesis of polysaccharides.
The following points are made by C.R. Bertozzi and L.L. Kiessling (Science 2001 291:2357):
1) The authors point out that oligosaccharides and glycoconjugates (glycoproteins and glycolipids) have intrigued biologists for decades as mediators of complex cellular events, and that with respect to structural diversity, oligosaccharides have the capacity to far exceed proteins and nucleic acids. This structural variance allows oligosaccharides to encode information for specific molecular recognition and to serve as determinants of protein folding, protein stability, and pharmacokinetics. Given that glycosylation is one of the most ubiquitous forms of post-synthesis ("posttranslational") protein modification, the unexpectedly small number of genes now apparent in the initial analysis of the human genome provides even more impetus for understanding the biological roles of oligosaccharides.
2) The authors point out that although oligosaccharide functions are now being elucidated in molecular detail, advances in glycobiology have been slow when compared to advances in protein and nucleic acid biochemistry. The same structural diversity in oligosaccharides that has captivated biologists has also frustrated efforts to define oligosaccharide expression patterns and to correlate structure with function. Some technical challenges are analytic in nature: determination of the oligosaccharide sequence in a specific glycoconjugate is still far from routine. Other difficulties originate in the nature of glycoconjugate biosynthesis, which is neither template-driven nor under direct genome (transcriptional) control. Oligosaccharides are assembled in step-wise fashion primarily in the endoplasmic reticulum and Golgi apparatus, a process involving significant microheterogeneity. As a result, it is difficult to obtain homogeneous and chemically defined glycoconjugates from biological sources. Without such materials in hand, biological functions are difficult to unravel.
3) The authors point out that genetic approaches have contributed significantly to the understanding of oligosaccharide function. The availability of entire genome sequences has revealed the multiplicity of enzymes that contribute to glycoconjugate assembly. Genetic deletion of such enzymes in model organisms has provided substantial insight. For example, mice deficient in the enzyme alpha-mannosidase II express an altered array of nitrogen-linked glycans on their cell-surface glycoproteins, and such mice are prone to a systemic *autoimmune response, which suggests that abnormalities in N-glycosylation in humans may be a factor in the pathogenesis of autoimmune diseases. Unfortunately, cell-surface presentation of simple as well as complex glycans requires many genes to be expressed in concert, and this complicates the analysis of single-gene mutations.
Science http://www.sciencemag.org
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Notes
extracellular matrix: In general, the extracellular matrix is a layer consisting mainly of proteins and glycosaminoglycans that form a sheet underlying endothelial and epithelial cells. The molecular constituents of the matrix are secreted by cells in the vicinity. Endothelial cells are the cells that line blood vessels.
eukaryotic cells: In general, cells that contain internal membrane-bound organelles.
ribosomes: A ribosome (not to be confused with riboZYME) is a small particle, a complex of various ribonucleic acid component subunits and proteins that functions as the site of protein synthesis.
autoimmune response: (autoimmune disease) In general, any pathology that involves a self-immunological process against the individual's own cells or tissues. Classified as human autoimmune diseases are rheumatoid arthritis, systemic lupus erythematosus, rheumatic fever, Addison's disease, multiple sclerosis, type 1 diabetes mellitus, etc.
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