Biological roles of oligosaccharides: all of the theories are correct
TL;DR: The only common features of the varied functions of oligosaccharides are that they either mediate ‘specific recognition’ events or that they provide ‘modulation’ of biological processes.
Abstract: Many different theories have been advanced concerning the biological roles of the oligosaccharide units of individual classes of glycoconjugates. Analysis of the evidence indicates that while all of these theories are correct, exceptions to each can also be found. The biological roles of oligosaccharides appear to span the spectrum from those that are trivial, to those that are crucial for the development, growth, function or survival of an organism. Some general principles emerge. First, it is difficult to predict a priori the functions a given oligosaccharide on a given glycoconjugate might be mediating, or their relative importance to the organism. Second, the same oligosaccharide sequence may mediate different functions at different locations within the same organism, or at different times in its ontogeny or life cycle. Third, the more specific and crucial biological roles of oligosaccharides are often mediated by unusual oligosaccharide sequences, unusual presentations of common terminal sequences, or by further modifications of the sugars themselves. However, such oligosaccharide sequences are also more likely to be targets for recognition by pathogenic toxins and microorganisms. As such, they are subject to more intra- and inter-species variation because of ongoing host-pathogen interactions during evolution. In the final analysis, the only common features of the varied functions of oligosaccharides are that they either mediate 'specific recognition' events or that they provide 'modulation' of biological processes. In so doing, they generate much of the functional diversity required for the development and differentiation of complex organisms, and for their interactions with other organisms in the environment.
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TL;DR: The division of synthesis and processing between the ER and the Golgi complex represents an evolutionary adaptation that allows efficient exploitation of the potential of oligosaccharides.
Abstract: N-linked oligosaccharides arise when blocks of 14 sugars are added cotranslationally to newly synthesized polypeptides in the endoplasmic reticulum (ER). These glycans are then subjected to extensive modification as the glycoproteins mature and move through the ER via the Golgi complex to their final destinations inside and outside the cell. In the ER and in the early secretory pathway, where the repertoire of oligosaccharide structures is still rather small, the glycans play a pivotal role in protein folding, oligomerization, quality control, sorting, and transport. They are used as universal “tags” that allow specific lectins and modifying enzymes to establish order among the diversity of maturing glycoproteins. In the Golgi complex, the glycans acquire more complex structures and a new set of functions. The division of synthesis and processing between the ER and the Golgi complex represents an evolutionary adaptation that allows efficient exploitation of the potential of oligosaccharides.
2,299 citations
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TL;DR: From a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells.
Abstract: From a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells. The sugars are added to nascent proteins as a core oligosaccharide unit, which is then extensively modified by removal and addition of sugar residues in the endoplasmic reticulum (ER) and the Golgi complex. It has become evident that the modifications that take place in the ER reflect a spectrum of functions related to glycoprotein folding, quality control, sorting, degradation, and secretion. The glycans not only promote folding directly by stabilizing polypeptide structures but also indirectly by serving as recognition "tags" that allow glycoproteins to interact with a variety of lectins, glycosidases, and glycosyltranferases. Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as alpha-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation. Each residue in the core oligosaccharide and each step in the modification program have significance for the fate of newly synthesized glycoproteins.
1,945 citations
TL;DR: It is demonstrated that deriving dihedral parameters by fitting to QM data for internal rotational energy curves for representative small molecules generally leads to correct rotamer populations in molecular dynamics simulations, and that this approach removes the need for phase corrections in the dihedral terms.
Abstract: A new derivation of the GLYCAM06 force field, which removes its previous specificity for carbohydrates, and its dependency on the AMBER force field and parameters, is presented. All pertinent force field terms have been explicitly specified and so no default or generic parameters are employed. The new GLYCAM is no longer limited to any particular class of biomolecules, but is extendible to all molecular classes in the spirit of a small-molecule force field. The torsion terms in the present work were all derived from quantum mechanical data from a collection of minimal molecular fragments and related small molecules. For carbohydrates, there is now a single parameter set applicable to both alpha- and beta-anomers and to all monosaccharide ring sizes and conformations. We demonstrate that deriving dihedral parameters by fitting to QM data for internal rotational energy curves for representative small molecules generally leads to correct rotamer populations in molecular dynamics simulations, and that this approach removes the need for phase corrections in the dihedral terms. However, we note that there are cases where this approach is inadequate. Reported here are the basic components of the new force field as well as an illustration of its extension to carbohydrates. In addition to reproducing the gas-phase properties of an array of small test molecules, condensed-phase simulations employing GLYCAM06 are shown to reproduce rotamer populations for key small molecules and representative biopolymer building blocks in explicit water, as well as crystalline lattice properties, such as unit cell dimensions, and vibrational frequencies.
1,751 citations
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TL;DR: The goal of this review is to describe those stimulators and inhibitors of angiogenesis that have been best-characterized.
Abstract: Proliferation of blood vessels is a process necessary for the nonnal growth and development of tissue (36). In the adult, angiogenesis occurs infrequently. Exceptions are found in the female reproductive system, where angiogenesis occurs in the follicle during its development, in the corpus luteum during ovulation, and in the placenta after pregnancy. These periods of angiogenesis are relatively brief and tightly regulated. Nonnal angiogenesis also occurs as part of the body's repair processes, e.g. in the healing of wounds and fractures. By contrast, uncontrolled angiogenesis can often be pathological. For example, the growth of solid tumors depends on vascularization (37), and in diabetic retinopathy vascularization of the retina often leads to blindness. Given the physiologic and pathological importance of angiogenesis, much effort in the last twenty years has been devoted to the isolation, characteriza tion, and purification of factors that can either stimulate or inhibit an giogenesis. Several bioassays have been developed to measure angiogenesis. The most common ones are endothelial cell migration (47) and proliferation (38) in vitro, and capillary growth in vivo in the developing chick chorioallantoic membrane (CAM) (4) and the cornea (45). The goal of this review is to describe those stimulators and inhibitors of angiogenesis that have been best-characterized.
990 citations
TL;DR: A striking evolutionary pattern in the expression of alpha-galactosyl epitopes on mammalian nucleated cells is observed, and an anomalous activity of this enzyme in man may result in initiation of autoimmune diseases because of the de novo expression of Gal alpha 1----3Gal beta 1----4GlcNAc-R epitopes recognized by anti-Gal.
915 citations
TL;DR: A brief overview of lymphocyte homing mechanisms can be found in this article, focusing on the adhesive interactions involved in lymphocyte-endothelial cell recognition and in the selective extravasation of lymphocytes populations into secondary and tertiary lymphoid tissues.
Abstract: The lymphoid system is functionally compartmentalized in vivo into discrete primary, secondary, and tertiary lymphoid organs. Primary lymphoid tissues--the bone marrow and thymus--are responsible for the production of mature "virgin" lymphocytes. Secondary lymphoid tissues--lymph nodes, the spleen, and gut-associated lymphoid tissues--are specialized for the accumulation and presentation of antigen to both virgin and memory lymphocyte subsets. The remainder of the body's tissues may be considered "tertiary" lymphoid tissues, in that they normally contain only a few lymphoid elements, but in the setting of inflammation can be induced to recruit unique subsets of primarily memory lymphocytes. Each lymphoid tissue is further subdivided into discrete microenvironments, each characterized by a distinct complement of lymphocyte subsets and stromal cells. Lymphocyte homing comprises the physiologic processes by which lymphocytes seek out and localize to particular tissues and to specific microenvironments therein. Homing mechanisms play a major role in the maintenance of these specialized microenvironments and are critical for the dispersal and targeting of naive and memory lymphocyte populations that are required for effective immune surveillance. Here, we provide a brief overview of mechanisms thought to control the homing of lymphocyte populations in vivo, focusing in particular on the adhesive interactions involved in lymphocyte-endothelial cell recognition and in the selective extravasation of lymphocyte populations into secondary and tertiary lymphoid tissues.
691 citations
TL;DR: The recruitment of neutrophils to sites of inflammation is initiated by the local production of bacteria-derived attractants, inflammatory cytokines, and other host-derived factors.
Abstract: THE recruitment of neutrophils to sites of inflammation is initiated by the local production of bacteria-derived attractants, inflammatory cytokines, and other host-derived factors. These factors i...
505 citations