Abstract:Genetic evidence suggests that the Schistosoma mansoni genome contains six genes that encode α1,3-fucosyltransferases (smFuTs). To date, the activities and specificities of these putative fucosyltransferases are unknown. As Schistosoma express a variety of fucosylated glycans, including the Lewis X antigen Galβ1-4(Fucα1-3)GlcNAcβ-R, it is likely that this family of genes encode enzymes that are partly responsible for the generation of those structures. Here, we report the molecular cloning of fucosyltransferas… Show more
“…After sequencing of the S. mansoni genome in 2009 various putative SmFucT coding sequences were found, of which 14 full-length genes could be amplified from cDNA 20 , 25 . Currently, these SmFucTs are characterized based on sequence analysis 20 and SmFucTF is the only functionally characterized enzyme based on chemoenzymatic assays 21 . However, characterization based on sequences or chemoenzymatic assays can differ from the in vivo biological function.…”
Section: Discussionmentioning
confidence: 99%
“…6 ). Furthermore, we attribute a new function to SmFucTF, since it is involved in the synthesis of F-LDN-F besides LeX 21 . Figure 6 Graphical representation of glycan motifs synthesized by S. mansoni fucosyltransferases (SmFucTs).…”
Section: Discussionmentioning
confidence: 99%
“…Several studies have analyzed the transcription levels of multiple SmFucTs in order to predict which enzyme is responsible for the synthesis of specific glycan motifs. However, comparison between these studies is difficult because of selected life stages and recurrent changes in accession numbers 20 , 21 , 26 . An extensive transcriptomic life cycle analysis performed by Fitzpatrick and colleagues showed differential expression of smp_054300, smp_137740 and smp_137730 26 , which are sequences related to SmFucTD, SmFucTE and SmFucTF, respectively.…”
Section: Discussionmentioning
confidence: 99%
“…The other 12 SmFucTs (A-F and H-M) are divided into two groups, based on the type of linkage formed upon fucose transfer (either α1,3 or α1,6). To date, only SmFucTF has been functionally characterized and was shown to synthesize LeX in chemoenzymatic assays with various glycan acceptors 21 .…”
Helminth parasites secrete a wide variety of immunomodulatory proteins and lipids to dampen host immune responses. Many of these immunomodulatory compounds are modified with complex sugar structures (or glycans), which play an important role at the host–parasite interface. As an example, the human blood fluke Schistosoma mansoni produces highly fucosylated glycan structures on glycoproteins and glycolipids. Up to 20 different S. mansoni fucosyltransferase (SmFucT) genes can be found in genome databases, but thus far only one enzyme has been functionally characterized. To unravel the synthesis of highly fucosylated N-glycans by S. mansoni, we examined the ability of ten selected SmFucTs to modify N-glycans upon transient expression in Nicotiana benthamiana plants. All enzymes were localized in the plant Golgi apparatus, which allowed us to identify the SmFucTs involved in core fucosylation and the synthesis of complex antennary glycan motifs. This knowledge provides a starting point for investigations into the role of specific fucosylated glycan motifs of schistosomes in parasite-host interactions. The functionally characterized SmFucTs can also be applied to synthesize complex N-glycan structures on recombinant proteins to study their contribution to immunomodulation. Furthermore, this plant expression system will fuel the development of helminth glycoproteins for pharmaceutical applications or novel anti-helminth vaccines.
“…After sequencing of the S. mansoni genome in 2009 various putative SmFucT coding sequences were found, of which 14 full-length genes could be amplified from cDNA 20 , 25 . Currently, these SmFucTs are characterized based on sequence analysis 20 and SmFucTF is the only functionally characterized enzyme based on chemoenzymatic assays 21 . However, characterization based on sequences or chemoenzymatic assays can differ from the in vivo biological function.…”
Section: Discussionmentioning
confidence: 99%
“…6 ). Furthermore, we attribute a new function to SmFucTF, since it is involved in the synthesis of F-LDN-F besides LeX 21 . Figure 6 Graphical representation of glycan motifs synthesized by S. mansoni fucosyltransferases (SmFucTs).…”
Section: Discussionmentioning
confidence: 99%
“…Several studies have analyzed the transcription levels of multiple SmFucTs in order to predict which enzyme is responsible for the synthesis of specific glycan motifs. However, comparison between these studies is difficult because of selected life stages and recurrent changes in accession numbers 20 , 21 , 26 . An extensive transcriptomic life cycle analysis performed by Fitzpatrick and colleagues showed differential expression of smp_054300, smp_137740 and smp_137730 26 , which are sequences related to SmFucTD, SmFucTE and SmFucTF, respectively.…”
Section: Discussionmentioning
confidence: 99%
“…The other 12 SmFucTs (A-F and H-M) are divided into two groups, based on the type of linkage formed upon fucose transfer (either α1,3 or α1,6). To date, only SmFucTF has been functionally characterized and was shown to synthesize LeX in chemoenzymatic assays with various glycan acceptors 21 .…”
Helminth parasites secrete a wide variety of immunomodulatory proteins and lipids to dampen host immune responses. Many of these immunomodulatory compounds are modified with complex sugar structures (or glycans), which play an important role at the host–parasite interface. As an example, the human blood fluke Schistosoma mansoni produces highly fucosylated glycan structures on glycoproteins and glycolipids. Up to 20 different S. mansoni fucosyltransferase (SmFucT) genes can be found in genome databases, but thus far only one enzyme has been functionally characterized. To unravel the synthesis of highly fucosylated N-glycans by S. mansoni, we examined the ability of ten selected SmFucTs to modify N-glycans upon transient expression in Nicotiana benthamiana plants. All enzymes were localized in the plant Golgi apparatus, which allowed us to identify the SmFucTs involved in core fucosylation and the synthesis of complex antennary glycan motifs. This knowledge provides a starting point for investigations into the role of specific fucosylated glycan motifs of schistosomes in parasite-host interactions. The functionally characterized SmFucTs can also be applied to synthesize complex N-glycan structures on recombinant proteins to study their contribution to immunomodulation. Furthermore, this plant expression system will fuel the development of helminth glycoproteins for pharmaceutical applications or novel anti-helminth vaccines.
“…20–22 DC-SIGN (dendritic cell specific ICAM grabbing non-integrin) is a counter-receptor to many Le X bearing glycoproteins, including CEACAM-1, Mac-1 and ICAM3, as well as unidentified Le X glycoproteins on invading pathogens and neutrophils. 2,7,9,23–27 In turn, the interaction of dendritic cells and neutrophils enables antigen-presenting cells to stimulate T cells and modulate adaptive immunity. Despite the critical role of DC-SIGN in the recognition of invading pathogens, human immunodeficiency virus (HIV), hepatitis C virus, and Mycobacterium tuberculosis , also use DC-SIGN to escape the immune response.…”
Lewis X (LeX) is a branched trisaccharide Galβ1→4(Fucα1→3)GlcNAc that is expressed on many cell surface glycoproteins and plays critical roles in innate and adaptive immune responses. However, efficient synthesis of glycopeptides bearing LeX remains a major limitation for structure-function studies of the LeX determinant. Here we report a total synthesis of a LeX pentasaccharide 1 using a regioselective 1-benzenesulfinyl piperidine/triflic anhydride promoted [3+2] glycosylation. The presence of an Fmoc-threonine amino acid facilitates incorporation of the pentasaccharide in solid phase peptide synthesis, providing a route to diverse O-linked LeX glycopeptides. The described approach is broadly applicable to the synthesis of a variety of complex glycopeptides containing O-linked LeX or sialyl LewisX (sLeX).
C-type lectins (CTLs) represent the most complex family of animal/human lectins that comprises 17 different groups. During evolution, CTLs have developed by diversification to cover a broad range of glycan ligands. However, ligand binding by CTLs is not necessarily restricted to glycans as some CTLs also bind to proteins, lipids, inorganic molecules, or ice crystals. CTLs share a common fold that harbors a Ca for contact to the sugar and about 18 invariant residues in a phylogenetically conserved pattern. In vertebrates, CTLs have numerous functions, including serum glycoprotein homeostasis, pathogen sensing, and the initiation of immune responses. Myeloid CTLs in innate immunity are mainly expressed by antigen-presenting cells and play a prominent role in the recognition of a variety of pathogens such as fungi, bacteria, viruses, and parasites. However, myeloid CTLs such as the macrophage inducible CTL (Mincle) or Clec-9a may also bind to self-antigens and thus contribute to immune homeostasis. While some CTLs induce pro-inflammatory responses and thereby lead to activation of adaptive immune responses, other CTLs act as inhibitory receptors and dampen cellular functions. Since CTLs are key players in pathogen recognition and innate immunity, targeting CTLs may be a promising strategy for cell-specific delivery of drugs or vaccine antigens and to modulate immune responses.
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