Many hosts-pathogen interactions are often mediated by carbohydrates by the interplay between glycans and glycan binding protein (GBP). Glycans on the host cells may be bound by the pathogen GBP and glycans on the pathogens may be bound by the GBP on the host cells. Some pathogens can even take advantage of the host cell defense mechanisms to promote their survival.
Typical bacterial glycoconjugates, lipopolysaccharide (LPS) and peptidoglycan (PGN), which ubiquitously occur in a wide range of bacterial cells as important components of their cell envelope, have long been known to enhance the immunological responses of higher animals. Synthetic works and related biological investigations on LPS are reviewed which were performed to understand the molecular basis of this phenomena mainly by the author’s and collaborating groups. Structural study followed by chemical synthesis of glycolipid part of LPS, named lipid A, proved it to exhibit all the biological activity described for LPS. Synthetic homogeneous lipid A and its derivatives were utilized for precise studies of their biological functions and interaction with receptor proteins. Similar research on PGN led to conclude its minimum active structure as muramyl dipeptide. Chemical synthesis gave unequivocal evidences for the concept that definite small molecular parts of LPS and PGN are recognized by its specific receptors and trigger our defense system which is now recognized as innate immunity.
The fields of “Glycobiology” and “Glycotechnology” are gaining an increasing amount of attention. A major part of my research has been directed at the synthesis and functional analysis of glycoconjugate oligosaccharides of various origins. In this mini-review, I wish to summarize my research history in carbohydrate chemistry of the last 12 years. Representative subjects have been 1) synthetic studies on Asn-linked glycan chains, 2) synthesis of novel glycoprotein structures, 3) approaches to polymer-support synthesis of oligosaccharides, 4) development of new reactions for the synthesis of glycoprotein-related molecules, 5) studies on the synthesis of glycoproteins, 6) analyses of glycoprotein processing and protein quality control system, 7) synthesis of glycosyltransferase inhibitors, 8) synthesis of biologically active glycolipids, and 9) synthesis and biological activities on mycobacterial cell wall components.
Animal lectins have contributed greatly to under-standing of the physiological significance of glycans in man and animals. Mannan-binding protein (MBP) binds to mannose, N-acetylglucosamine and L-fucose via the carbohydrate binding sites in its carbohydrate recognition domain (CRD). In pathogenic microorganisms, manno-oligosaccharides on the cell surface appear to be the major glycans involved in the interaction with MBP, whereas in human colorectal carcinoma SW1116 cells, which are endogenous target cells of MBP, Lewis (Le)-type oligosaccharides with the type I structure appear to play a major role in the interaction with the lectin. In fact, MBP ligand oligosaccharides (MLO), which have complex type N-glycans with at least 4 Fuc(Hex-HexNAc) units, have been isolated with an MBP affinity column, whereas complex type N-glycans having 3 or less Fuc(Hex-HexNAc) units as well as high-mannose type structures (Man5 to Man8) did not bind to the MBP affinity column. The structures of MLO are very unique and distinct from those of other previously reported tumor-specific carbohydrate antigens, and thus should be considered as representative of a new family of tumor-associated carbohydrate antigens. The reasons why and how MLO exhibits such strong affinity to MBP are not clear at present but computer modeling suggested the possibility that a MBP-Lewis oligosaccharides complex may be formed between the trimeric structure of the carbohydrate recognition domain (CRD) and Leb-(Lea)x4-Lex, a typical example of the nonreducing terminal oligosaccharide structure of MLO.
Most proteins within living organisms contain glycans. Glycan structures can modulate the biological properties and functions of glycoproteins. The major glycans of glycoproteins can be classified into two groups, N-glycans and O-glycans, according to their glycan-peptide linkage regions. This review will give an outline of the O-mannosyl glycans; structure, biosynthesis, function, and pathology.
Sialidases are glycosidases catalyzing the removal of α-glycosidically linked sialic acid residues from carbohydrate groups of glycoproteins and glycolipids. The removal of sialic acids is the initial step in degradation of such glycoconjugates.However, sialidases of mammalian origin may also be involved in many biological processes other than lysosomal catabolism. Four types of mammalian sialidases have been identified and characterized to date, designated as Neu1, Neu2, Neu3 and Neu4. They differ in major subcellular localization and enzymatic properties including substrate specificity, and each has been found to play a unique role depending on its particular properties. A large body of evidence for their contribution to cellular events including differentiation, growth and apoptosis has now accumulated. The present review attempts to briefly summarize physiological and pathological roles of mammalian sialidases.