The shape of a glycan will be determined by the conformation of the furanose/ pyranose rings and the relative positioning of the rings in the chain. Based on x-ray crystallography, neutron diffraction, and homonuclear coupling constant data the 4Cj chair conformer ('C4 for L-sugars) is the energetically preferred pyranose ring structure (Abeygunawardana and Bush, 1993; Brown and Levy, 1965). In rare cases, for example, for L-iduronic acid as constituent of heparan and dermatan sulfates, and to accommodate mechanical stress, conformational flexibility and elasticity of a pyranose can be generated by chair-boat transitions, which allow L-iduronic acid to acquire the skew-boat form 2So (Casu et al., 1988; Marszalek et al., 1998). Yet the main contribution to define a glycan's shape will generally originate not
Fig. 3 Depiction of the main source of conformational flexibility of the disaccharide Galp1-3Gal (see Fig. 1) by independent rotations about the two dihedral angles 0 and y of the glycosidic bond
Fig. 3 Depiction of the main source of conformational flexibility of the disaccharide Galp1-3Gal (see Fig. 1) by independent rotations about the two dihedral angles 0 and y of the glycosidic bond from this source. In contrast, it will arise from changes of the two dihedral angles 0 and y of each glycosidic bond (Fig. 3).
By letting the thumbs of each hand touch, independent variations of these two parameters by movements of the hands can swiftly be visualized. Since the pyranose rings linked by the glycosidic bond and their exocyclic substituents are rather bulky, their size will impose topological restraints to the intramolecular movements of the oligomer. Compared to oligopeptides with small side chains, the conformational space accessible to the molecule at room temperature will thus be relatively restricted. That this spatial factor limits the range of interchangeable conformations has been inferred by computer-assisted molecular mechanics and dynamics calculations and convincingly documented by experimental evidence primarily from sophisticated NMR-spectroscopy (Bush et al., 1999; Imberty, 1997; Siebert et al., 1999; von der Lieth et al., 1997a, 1998; Woods, 1998). Exploring the actual position(s) of each oligosaccharide on the scale between high flexibility with an ensemble of conformers and almost complete rigidity will definitely have salient implications to predict its role as coding unit. In this respect, it is also worth pointing out that a notable level of intramolecular flexibility is not a favorable factor for crystallization. Indeed, such an extent of unrestrained conformational entropy can contribute to explain the frequently frustrating experience in respective attempts in carbohydrate chemistry. If on the other hand the level of conformational entropy is confined to only very few stable conformers (keys), the presented shape distribution is not only a function of the sequence but also of external factors affecting the actual status of the equilibrium. In this context it should not escape notice that environmental parameters with impact on presentation of the glycan in glycoconjugates might shift the dynamic equilibrium of shape interconversions between attainable positions without requirement to alter the primary structure. Sugar receptors as probes for distinguishing bioactive or bioinert glycan presentation modes on proteins have already given the hypothesis experimental credit (Mann and Waterman, 1998; Noorman et al., 1998; Solis et al., 1987; White et al., 1997). This support brings to view an attractive means to modify shape, which warrants contriving further appropriate experiments to underpin its actual operation beyond any doubt.
As implied by referring to a code system, information stored as sequence and shape will have to be grasped. Translating and transmitting it into intended responses is the task of decoding devices. They should specifically recognize coding units established by glycans. Thus, in addition to physicochemically serving roles to control folding, oligomerization and access of proteolytic enzymes, as already mentioned (Drickamer and Taylor, 1998; Gagneux and Varki, 1999; Reuter and Gabius, 1999; Sharon and Lis, 1997; Varki, 1996), oli-gosaccharides in glycan chains can be likened to the postal code in an address to convey distinct messages read by suitable receptors. These carbohydrate-binding proteins are classified into enzymes responsible to assemble, modify, and degrade sugar structures, immunoglobulins homing in on carbohydrates as antigens, and, last but not least, lectins. Evidently, the third class encompasses all carbohydrate-binding proteins, which are neither antibodies nor are they enzymes which couple ligand recognition with catalytic activity to process the target (Barondes, 1988; Gabius, 1994). That lectin/glycan recognition has been assigned pivotal duties in an organism can at best be rendered perceptible by aberrations causing diseases. Knowledge accrued from the study of the biochemical basis of human diseases (e.g. mucolipidosis II or leukocyte adhesion deficiency (LAD) type II syndrome) underscores how trafficking of lysosomal enzymes or leukocytes can go awry owing to a lack of generation of the essential carbohydrate signal (Brockhausen et al., 1998; Lee and Lee, 1996; Paulson, 1996; Reuter and Gabius, 1999; Schachter, 1999; von Figura, 1990).
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