The 5-Deoxy-5-methylthio-xylofuranose Residue in Mycobacterial Lipoarabinomannan. Absolute Stereochemistry, Linkage Position, Conformation, and Immunomodulatory Activity (original) (raw)
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Carbohydrate Research, 1998
An improved synthesis of propyl 4-O-(3,6-di-O-methyl-d-glucopyranosyl)-2,3-di-O-methyl-l-rhamnopyranoside, a disaccharide corresponding to the phenolic glycolipid of Mycobacterium leprae using a trichloroacetimidate as a glycosyl donor is described. The synthetic strategy is also applied to the preparation of three corresponding disaccharide analogues containing 13 C-labeled methyl groups. The preparation of the trisaccharide, propyl 2-O-[4-O-(3,6-di-O-methyl-d-glucopyranosyl)-2,3-di-O-methyl-l-rhamnopyranosyl]-3-O-methyl-l-rhamnopyranoside is also reported. The di-and tri-saccharides were characterized by 1 H and 13 C NMR spectroscopy.
Journal of Biological Chemistry, 2002
Lipomannan (LM) and lipoarabinomannan (LAM) are major glycolipids present in the mycobacterial cell wall that are able to modulate the host immune response. In this study, we have undertaken the structural determination of these important modulins in Mycobacterium chelonae, a fast growing pathogenic mycobacterial species. One-dimensional and two-dimensional NMR spectra were used to demonstrate that LM and LAM from M. chelonae, designated CheLM and CheLAM, respectively, possess structures that differ from the ones reported earlier in other mycobacterial species. Analysis by gas chromatography/mass spectrometry of the phosphatidyl-myo-inositol anchor, which is thought to play a role in the biological functions of these lipoglycans, pointed to a high degree of heterogeneity based on numerous combinations of acyl groups on the C-1 and C-2 positions of the glycerol moiety. Characterization of the mannan core of CheLM and CheLAM revealed the presence of novel ␣1,3-mannopyranosyl side chains. This motif, which reacted specifically with the lectin from Galanthus nivalis, was found to be unique among a panel of nine mycobacterial species. Then, CheLM and CheLAM were found to be devoid of both the mannooligosaccharide cap present in Mycobacterium tuberculosis and the inositol phosphate cap present in Mycobacterium smegmatis and other fast growing species. Tumor necrosis factor-␣ and interleukin-8 production were assessed from human macrophages with LAM preparations from different species. Our results suggest that the inositol phosphate capping may represent the major cytokineinducing component of LAMs. This work not only underlines the diversity of LAM structures among various mycobacterial species but also provides new structures that could be useful to dissect the structure-function relationships of these complex molecules.
ACS chemical biology, 2017
An array of homogenous glycans representing all the major carbohydrate structures present in the cell wall of the human pathogen Mycobacterium tuberculosis and other mycobacteria has been probed with a panel of glycan-binding receptors expressed on cells of the mammalian innate immune system. The results provide an overview of interactions between mycobacterial glycans and receptors that mediate uptake and survival in macrophages, dendritic cells and sinusoidal endothelial cells. A subset of the wide variety of glycan structures present on mycobacterial surfaces interact with cells of the innate immune system through the receptors tested. Endocytic receptors, including the mannose receptor, DC-SIGN, langerin, and DC-SIGNR (L-SIGN), interact predominantly with mannose-containing caps found on the mycobacterial polysaccharide lipoarabinomannan. Some of these receptors also interact with phosphatidyl-myo-inositol mannosides and mannose-containing phenolic glycolipids. Many glycans are ...
Journal of the American Chemical Society, 2010
Although lipo-oligosaccharides (LOSs) are recognized as major parietal components in many mycobacterial species, their involvement in the host-pathogen interactions have been scarcely documented. In particular, the biological implications arising from the high degree of structural species-specificity of these glycolipids remain largely unknown. Growing recognition of the Mycobacterium marinum-Danio rerio as a specific host-pathogen model devoted to the study of the physiopathology of mycobacterial infections prompted us to elucidate the structure-to-function relationships of the elusive end-product, LOS-IV, of the LOS biosynthetic pathway in M. marinum. Combination of physicochemical and molecular modeling methods established that LOS-IV resulted from the differential transfer on the caryophyllose-containing LOS-III of a family of very unusual N-acylated monosaccharides, naturally present as different diastereoisomers. In agreement with the partial loss of pathogenecity previously reported in a LOS-IV-deficient M. marinum mutant, we demonstrated that this terminal monosaccharide conferred to LOS-IV important biological functions, including macrophage activating properties.
The Journal of Immunology, 2009
Mycobacterium tuberculosis possesses a variety of immunomodulatory factors that influence the host immune response. When the bacillus encounters its target cell, the outermost components of its cell envelope are the first to interact. Mycobacteria, including M. tuberculosis, are surrounded by a loosely attached capsule that is mainly composed of proteins and polysaccharides. Although the chemical composition of the capsule is relatively well studied, its biological function is only poorly understood. The aim of this study was to further assess the functional role of the mycobacterial capsule by identifying host receptors that recognize its constituents. We focused on ␣-glucan, which is the dominant capsular polysaccharide. Here we demonstrate that M. tuberculosis ␣-glucan is a novel ligand for the C-type lectin DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin). By using related glycogen structures, we show that recognition of ␣-glucans by DC-SIGN is a general feature and that the interaction is mediated by internal glucosyl residues. As for mannose-capped lipoarabinomannan, an abundant mycobacterial cell wall-associated glycolipid, binding of ␣-glucan to DC-SIGN stimulated the production of immunosuppressive IL-10 by LPS-activated monocytederived dendritic cells. By using specific inhibitors, we show that this IL-10 induction was DC-SIGN-dependent and also required acetylation of NF-B. Finally, we demonstrate that purified M. tuberculosis ␣-glucan, in contrast to what has been reported for fungal ␣-glucan, was unable to activate TLR2.
FEMS Microbiology Reviews, 2011
Approximately one third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. This bacterium has an unusual lipid-rich cell wall containing a vast repertoire of antigens, providing a hydrophobic impermeable barrier against chemical drugs, thus representing an attractive target for vaccine and drug development. Apart from the mycolyl-arabinogalactan-peptidoglycan complex, mycobacteria possess several immunomodulatory constituents, notably lipomannan and lipoarabinomannan. The availability of whole-genome sequences of M. tuberculosis and related bacilli over the past decade has led to the identification and functional characterization of various enzymes and the potential drug targets involved in the biosynthesis of these glycoconjugates. Both lipomannan and lipoarabinomannan possess highly variable chemical structures, which interact with different receptors of the immune system during host-pathogen interactions, such as Toll-like receptors-2 and C-type lectins. Recently, the availability of mutants defective in the synthesis of these glycoconjugates in mycobacteria and the closely related bacterium, Corynebacterium glutamicum, has paved the way for host-pathogen interaction studies, as well as, providing attenuated strains of mycobacteria for the development of new vaccine candidates. This review provides a comprehensive account of the structure, biosynthesis and immunomodulatory properties of these important glycoconjugates.
The Journal of Organic Chemistry, 2001
Syntheses of the ethyl glycosides of 5-O-(-D-galactofuranosyl)-D-galactofuranose and 5-O-(R-Darabinofuranosyl)-6-O-(-D-galactofuranosyl)-D-galactofuranose present in motifs D and E of Mycobacterium tuberculosis arabinogalactan, respectively, have been presented. The pentenylmediated O-glycosylation reaction was utilized to obtain the disaccharide of motif D. The first coupling reaction to prepare the inner disaccharide portion of motif E was accomplished by trichloroacetamidate method while the installation of the terminal sugar by pentenyl glycosylation approach was successful.