A high-density coding system is essential to allow cells to communicate efficiently and swiftly through complex surface interactions. All the structural requirements for forming a wide array of signals with a system of minimal size are met by oligomers of carbohydrates. These molecules surpass amino acids and nucleotides by far in information-storing capacity and serve as ligands in biorecognition processes for the transfer of information. The results of work aiming to reveal the intricate ways in which oligosaccharide determinants of cellular glycoconjugates interact with tissue lectins and thereby trigger multifarious cellular responses (e.g. in adhesion or growth regulation) are teaching amazing lessons about the range of finely tuned activities involved. The ability of enzymes to generate an enormous diversity of biochemical signals is matched by receptor proteins (lectins), which are equally elaborate. The multiformity of lectins ensures accurate signal decoding and transmission. The exquisite refinement of both sides of the protein-carbohydrate recognition system turns the structural complexity of glycans--a demanding but essentially mastered problem for analytical chemistry--into a biochemical virtue. The emerging medical importance of protein-carbohydrate recognition, for example in combating infection and the spread of tumors or in targeting drugs, also explains why this interaction system is no longer below industrial radarscopes. Our review sketches the concept of the sugar code, with a solid description of the historical background. We also place emphasis on a distinctive feature of the code, that is, the potential of a carbohydrate ligand to adopt various defined shapes, each with its own particular ligand properties (differential conformer selection). Proper consideration of the structure and shape of the ligand enables us to envision the chemical design of potent binding partners for a target (in lectin-mediated drug delivery) or ways to block lectins of medical importance (in infection, tumor spread, or inflammation).
Growing insights into the many roles of glycoconjugates in biorecognition as ligands for lectins indicates a need to compare plant and animal lectins. Furthermore, the popularity of plant lectins as laboratory tools for glycan detection and characterization is an incentive to start this review with a brief introduction to landmarks in the history of lectinology. Based on carbohydrate recognition by lectins, initially described for concanavalin A in 1936, the chemical nature of the ABH-blood group system was unraveled, which was a key factor in introducing the term lectin in 1954. How these versatile probes are produced in plants and how they are swiftly and efficiently purified are outlined, and insights into the diversity of plant lectin structures are also given. The current status of understanding their functions calls for dividing them into external activities, such as harmful effects on aggressors, and internal roles, for example in the transport and assembly of appropriate ligands, or in the targeting of enzymatic activities. As stated above, attention is given to intriguing parallels in structural/functional aspects of plant and animal lectins as well as to explaining caveats and concerns regarding their application in crop protection or in tumor therapy by immunomodulation. Integrating the research from these two lectin superfamilies, the concepts are discussed on the role of information-bearing glycan epitopes and functional consequences of lectin binding as translation of the sugar code (functional glycomics).
Theoretical calculations reveal that oligosaccharides are second to no other class of biochemical oligomery in terms of coding capacity. As integral part of cellular glycoconjugates they can serve as recognitive units for receptors (lectins). Having first been detected in plants, lectins are present ubiquitously. Remarkably for this field, they serve as bacterial and viral adhesins. Following a description of these branches of lectinology to illustrate history, current status and potential for medicinal chemistry, we document that lectins are involved in a wide variety of biochemical processes including intra- and intercellular glycoconjugate trafficking, initiation of signal transduction affecting e. g. growth regulation and cell adhesion in animals. It is thus justified to compare crucial carbohydrate epitopes with the postal code ensuring correct mail routing and delivery. In view of the functional relevance of lectins the design of high-affinity reagents to occupy their carbohydrate recognition domains offers the perspective for an attractive source of new drugs. Their applications can be supposed to encompass the use as cell-type-selective determinant for targeted drug delivery and as blocking devices in anti-adhesion therapy during infections and inflammatory disease. To master the task of devising custom-made glycans/glycomimetics for this purpose, the individual enthalpic and entropic contributions in the molecular rendezvous between the sugar receptor under scrutiny and its ligand in the presence of solvent molecules undergoing positional rearrangements need to be understood and rationally exploited. As remunerative means to this end, cleverly orchestrated deployment of a panel of methods is essential. Concerning the carbohydrate ligand, its topological parameters and flexibility are assessed by the combination of computer-assisted molecular-mechanics and molecular-dynamics calculations and NMR-spectroscopic measurements. In the presence of the receptor, the latter technique will provide insights into conformational aspects of the bound ligand and into spatial vicinity of the ligand to distinct side chains of amino acids establishing the binding site in solution. Also in solution, the hydrogen-bonding pattern in the complex can be mapped with monodeoxy and monofluoro derivatives of the oligosaccharide. Together with X-ray crystallographic and microcalorimetric studies the limits of a feasible affinity enhancement can be systematically probed. With galactoside-binding lectins as instructive mo del, recent progress in this area of drug design will be documented, emphasizing the general applicability of the outlined interdisciplinary approach.
The impact of desferrioxamine B (DFOB) on intracellular calcium mobilization, chemoluminescence (CL) signaling, phagocytosis, and bacterial killing of Yersinia enterocolitica by polymorphonuclear leukocytes (PMNL) was investigated. DFOB did not alter calcium signaling in PMNL but transiently increased phagocytosis. Likewise, higher counts of viable bacteria in PMNL and increased CL signals after stimulation with Y. enterocolitica were observed in the presence of DFOB. However, DFOB reduced the CL signal elicited individually by zymosan, PMA, and FMLP. Comparison of plasmid-cured with plasmid-harboring Y. enterocolitica revealed that plasmid-encoded determinants modulate phagocytosis, CL signal, and bactericidal properties of PMNL. These data demonstrate that DFOB alters microbicidal properties of PMNL and modulates their interaction with Y. enterocolitica and provide further evidence for a putative dual role of DFOB in the pathogenesis of Yersinia infection, namely growth support of the pathogen and modulation of the antimicrobial host response.
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