Glycobiology Advance Access originally published online on September 14, 2006
Glycobiology 2006 16(12):158R-184R; doi:10.1093/glycob/cwl040
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REVIEW |
Fucosylation in prokaryotes and eukaryotes
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
1 To whom correspondence should be addressed; e-mail: diane.taylor{at}ualberta.ca
Received on June 21, 2006; revised on August 25, 2006; accepted on August 25, 2006
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Abstract
IntroductionFucosylated carbohydrate structures are involved in a variety of biological and pathological processes in eukaryotic organisms including tissue development, angiogenesis, fertilization, cell adhesion, inflammation, and tumor metastasis. In contrast, fucosylation appears less common in prokaryotic organisms and has been suggested to be involved in molecular mimicry, adhesion, colonization, and modulating the host immune response. Fucosyltransferases (FucTs), present in both eukaryotic and prokaryotic organisms, are the enzymes responsible for the catalysis of fucose transfer from donor guanosine-diphosphate fucose to various acceptor molecules including oligosaccharides, glycoproteins, and glycolipids. To date, several subfamilies of mammalian FucTs have been well characterized; these enzymes are therefore delineated and used as models. Non-mammalian FucTs that possess different domain construction or display distinctive acceptor substrate specificity are highlighted. It is noteworthy that the glycoconjugates from plants and schistosomes contain some unusual fucose linkages, suggesting the presence of novel FucT subfamilies as yet to be characterized. Despite the very low sequence homology, striking functional similarity is exhibited between mammalian and Helicobacter pylori
1,3/4 FucTs, implying that these enzymes likely share a conserved mechanistic and structural basis for fucose transfer; such conserved functional features might also exist when comparing other FucT subfamilies from different origins. Fucosyltranferases are promising tools used in synthesis of fucosylated oligosaccharides and glycoconjugates, which show great potential in the treatment of infectious and inflammatory diseases and tumor metastasis. Key words: eukaryotes / fucosylation / FucTs / prokaryotes
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Introduction |
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Fucosyltransferases (FucTs) are widely expressed in vertebrates, invertebrates, plants, and bacteria. They belong to the glycosyltransferase superfamily (EC 2.4.1.x.y), which is defined in the category of Carbohydrate-Active enZYmes (CAZY) (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html). FucTs catalyze the inverting reaction in which a fucose residue is transferred from the donor guanosine-diphosphate fucose (GDP-Fuc) to the acceptor molecules including oligosaccharides, glycoproteins, and glycolipids (Oriol et al., 1999
). The fucosylated glycoconjugates are involved in a variety of biological and pathological processes.
FucT subfamilies
Based on the site of fucose addition, FucTs are classified into 1,2, 1,3/4, 1,6, and O-FucTs (Figures 1 and 2). The former three subfamilies of enzymes in eukaryotic organisms are type II transmembrane Golgi-anchored proteins containing an N-terminal cytoplasmic tail, a transmembrane domain, and an extended stem region followed by a large globular C-terminal catalytic domain facing the Golgi lumen (Nilsson et al., 1993, 1996) (Figure 3A). O-FucTs, however, are endoplasmic reticulum (ER)-localized soluble proteins and catalyze O-fucosylation in the ER (Luo and Haltiwanger, 2005; Okajima et al., 2005). An unusual non-Golgi 1,2 FucT in Dictyostelium is localized in both the cytoplasm and the nucleus and modifies Skp1 protein, a subunit of the SCF-E3 ubiquitin ligase (van Der Wel et al., 2001). This enzyme lacks any conserved 1,2 FucT motifs (see Sequence homology and structural prediction of FucT subfamilies) and is classified in CAZY family 74 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html).
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GDP-fucose synthesis and transport
GDP-Fuc is synthesized in the cytoplasm (Becker and Lowe, 2003
) through de novo synthesis and salvage pathways. De novo synthesis, accounting for 90% of the total GDP-Fuc production, is involved in converting GDP-mannose to GDP-Fuc via GDP-mannose 4,6-dehydrase (GMD) and GDP-keto-6-deoxymannaose 3,5-epimerase/4-reductase (also named FX) that contains dual activities (Tonetti et al., 1996) (Figure 4). The salvage pathway, accounting for approximately 10% of GDP-Fuc production, utilizes the free cytosolic fucose as substrate which is derived from an extracellular source or from lysosomal degradation (Becker and Lowe, 2003). Fucose is firstly phosphorylated by fucokinase to form fucose-1-phosphate, which is then converted to GDP-fucose by GDP-Fuc pyrophosphorylase (Niittymaki et al., 2004) (Figure 4). Subsequently, a GDP-Fuc transporter (Gft), anchored at the Golgi membrane (Figure 4), imports GDP-Fuc from the cytoplasm to the Golgi-lumen (Luhn et al., 2004), where GDP-Fuc becomes concentrated in vesicles and is recognized by Golgi-localized FucTs as a donor substrate (Hirschberg, 2001). Human Gft was reported to be a hydrophobic protein possessing ten transmembrane domains, with the amino and carboxy termini exposed to the cytosol (Hirschberg, 2001). Assembling into a homodimer, Gft couples GDP-Fuc import to the Golgi lumen with GMP export to the cytoplasm (Luhn et al., 2004; Helmus et al., 2006) (Figure 4). As O-FucTs are present and able to catalyze O-fucosylation in the ER (Luo and Haltiwanger, 2005; Okajima et al., 2005), one expects the presence of an ER-localized Gft, which has not yet been identified.
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1,2 Fucosylation
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1,2 FucTs transfer fucose at an 1,2 linkage from GDP-Fuc to the galactose moiety of Galß1,4GlcNAc (Type II, also called LacNAc) or Galß1,3GlcNAc (Type I) structures, which are localized at the peripheral (antennae) position of acceptor molecules (Figures 1 and 5). 1,2 FucTs, belonging to CAZY family 11 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html), were shown to adopt random bi bi mechanism for fucose transfer (Palcic et al., 1989).
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1,2 Fucosylation in mammals, Caenorhabditis elegans and Schistosoma mansoniIn the human genome, fut1, fut2, and sec1 (a pseudogene with a mutation causing a frameshift) encode the H, Se (secretor), and non-functional
1,2 FucTs, respectively. Products of fut1 is expressed mainly on erythrocyte membrane and vascular endothelium (Mollicone et al., 1995), whereas the fut2 is expressed on epithelial cells and in body fluids (i.e., saliva) (Avent, 1997). Human FUT1 and FUT2 are responsible for synthesis of H-antigen (Figure 5), and secretor status is determined by the secretor gene (fut2). Secretor-negative individuals, also called non-secretors, lack H-antigen and its derived structures in body exocrine tissues (Avent, 1997). Human blood group (H) and secretory (Se) 1,2 FucTs show different acceptor specificities; the former prefers Type I and Type II acceptors and is less efficient in fucose transfer to Galß1,3GalNAc (Type III) structures (Kyprianou et al., 1990; Sarnesto et al., 1990), whereas the latter is more active on Type I and Type III than on Type II acceptor (Sarnesto et al., 1990).
Among over two-dozen putative 1,2 FucTs from C. elegans, one of them, CE2FT-1, prefers the unusual sugars Galß1,4Xyl-R and Galß1,6GlcNAc-R as acceptors. CE2FT-1 is expressed in all developmental stages of C. elegans and shares only 5–10% sequence identity to 1,2 FucTs from human, rabbits, and mice (Zheng et al., 2002). It is unable to fucosylate Type III, Galß1,4Glcß-R, or lactose. Neither can it fucosylate acceptors that already contain an 1,3/4-linked fucose moiety (Zheng et al., 2002). Despite its unique features, CE2FT-1 is categorized into CAZY family 11 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html).
Notably, glycoconjugates of S. mansoni contain Fuc1,2 Fuc structures, indicating the existence of an 1,2 FucT that is capable of transferring Fuc to another Fuc residue (Marques et al., 2001). Such an 1,2 FucT from cercariae of the avian schistosome Trichobilharzia ocellata displayed a relatively low catalytic efficiency for the substrate Fuc1,3GlcNAcß1,2Man because of its high Km (Hokke et al., 1998). It is not yet known whether this schistosomal enzyme contains 1,2 FucT motifs (see Sequence homology and structural prediction of FucT subfamilies), and if it belongs to an as yet unidentified subfamily.
1,2 Fucosylation in bacteria
Several putative bacterial 1,2 FucTs have been identified to date, including proteins involved in colanic acid synthesis in Escherichia coli K12 and Salmonella enterica LT2 (Reeves et al., 2006), in O-antigen synthesis in Yersinia enterocolitica O8 (Reeves et al., 2006), the WbsJ in enteropathogenic E. coli O128 strain (Shao et al., 2003), and 1,2 FucTs from Helicobacter pylori (Wang, Boulton, et al., 1999; Wang, Rasko, et al., 1999). Of these enzymes, only H. pylori 1,2 FucTs have been functionally characterized (Wang, Boulton et al., 1999; Wang, Rasko, et al., 1999; Wang et al., 2000).
FucTs from H. pylori are responsible for the last steps in the synthesis of Lewis blood antigen structures on their lipopolysaccharide (LPS), which contains incompletely fucosylated repeating LacNAc chains (Chan et al., 1995; Sherburne and Taylor, 1995; Aspinall and Monteiro, 1996; Aspinall et al., 1996, 1997). More than 80% of H. pylori strains express Type II Lewis antigens (Lex and/or Ley), and half of them express both (Sherburne and Taylor, 1995; Aspinall and Monteiro, 1996; Wirth et al., 1996; Monteiro et al., 1998). A much smaller proportion of H. pylori strains express Type I Lewis blood group antigens (Lea and/or Leb) (Monteiro et al., 1998) and a very small number express sialyl-Lex (Wirth et al., 1996; Monteiro et al., 2000). Some H. pylori strains also possess O-antigens that show no reaction to antibodies against Lex, Ley, Lea, or Leb. These structures were designated non-typeable O-antigens (Rasko et al., 2001).
The gene encoding the 1,2 FucT in the H. pylori genome was named futC (Berg et al., 1997; Alm et al., 1999), which contains polyA–polyC slippery tracts at the 5' end. During DNA replication, the addition or deletion of one or more base pairs within these tracts occurs at a much higher rate than the normal mutation frequency (Appelmelk et al., 1998, 1999, 2000; Wang Boulton, et al., 1999; Wang, Rasko, et al., 1999; Wange et al., 2000). Moreover, futC contains imperfect TAA (or GAA or AAA) repeats immediately downstream of the poly C tract at the mid-region of the gene (Wang, Rasko, et al., 1999). The signature sequences, an internal Shine-Dalgarno-like context, a heptamer (AAAAAAG) and the downstream potential stem-loop structure, are also present, and they are hypermutable (Wang, Rasko, et al., 1999). During translation, the ribosome can slip to the –1 reading frame at a frequency of 50% to encode a full-length 1,2 FucT protein instead of two truncated products. Additionally, the futC gene in some H. pylori strains lacks a valid promoter region leading to lack of expression of an 1,2 FucT protein (Wang, Rasko, et al., 1999). Therefore, the on/off status of the futC gene can be controlled at both translational and transcriptional levels. The phenomenon of switching genes on and off by various genetic mechanisms is referred to as phase variation, which is a very common mechanism used by micro-organisms to switch on or off the expression of outer membrane proteins (Owen et al., 1996; Seifert, 1996; Bart et al., 1999; Neyrolles et al., 1999; Horino et al., 2003; Kyme et al., 2003; Zhang et al., 2004; Martin et al., 2005).
Unlike eukaryotic enzymes, H. pylori 1,2 FucTs lack the N-terminal cytosolic tail and the transmembrane domain (Wang, Boulton, et al., 1999). In fact, the 1,2 FucT from H. pylori strain UA802 was demonstrated to be a soluble protein located in the cytoplasm (Wang, Boulton, et al., 1999). 1,2 FucTs from different H. pylori strains share very high sequence identity with one another (
95%), but very low identity (18–22%) with their mammalian counterparts (Oriol et al., 1999).
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1,3/4 Fucosylation
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1,3/4 FucTs, belonging to CAZY family 10 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html), add fucose at 1,3 or 1,4 linkage to the GlcNAc moiety of Type II or Type I structures, which are localized at the peripheral (antennae) position of acceptor molecules (Oriol et al., 1999) (Figure 1). Kinetic studies suggested that human 1,3/4 FucTs employed an ordered sequential mechanism with donor GDP-Fuc binding first, followed by acceptor binding, and then product Lex being released followed by the GDP portion of the donor (Murray et al., 1996, 1997; Qiao et al., 1996).
1,3/4 Fucosylation in mammals
Mammalian 1,2 and 1,3/4 FucTs are involved in the last steps of synthesis of A, B, and H Lewis blood antigens and Lewis-related carbohydrate antigens (i.e., Lex, Ley, Lea, Leb, sialyl-Lex, and sialyl-Lea) (Figure 5). Difucosylated Lewis antigens (Ley and Leb) can be synthesized via two pathways: terminal fucosylation (in an 1,2 linkage) followed by subterminal fucosylation (in an 1,3 or 1,4 linkage) or subterminal fucosylation followed by terminal fucosylation. Mammalian cells predominantly use the former pathway (Henry et al., 1995).
Genes fut3–7 and fut9 in the human genome encode six 1,3/4 FucTs, abbreviated FUT3–7 and FUT9 (or Fuc-TIII–VII and Fuc-TIX), all of which have 1,3 activity, but FUT3 and FUT5 also possess 1,4 activity. Human 1,3/4 FucTs are Type II membrane proteins (Figure 3A). Domain swapping studies demonstrated that the extended stem region, also called the hypervariable region, of FUT3 and FUT5 confers 1,4 activity (Legault et al., 1995; Xu et al., 1996; Nguyen et al., 1998). Specifically, an aromatic residue (Trp) within this region determines Type I acceptor recognition (Dupuy et al., 1999, 2004). In animals, Lea seems to be exclusively present in primates (Costache et al., 1997; Dupuy et al., 2002). Human fut10 and fut11 were described to encode two proteins that contain the characteristic 1,3 motifs (see Sequence homology and structural prediction of FucT subfamilies) and share homology with 1,3 FucT from Drosophila (Roos et al., 2002). The function and the acceptor specificity of FUT10 and FUT11 have not yet been defined.
Human FUT3–7 and FUT are able to transfer fucose to acceptors that contain a poly-LacNAc chain, but they have different preferable fucosylation sites (Supplementary Table 1 Figure 1), although FUT3, 5, and 6 share about 85% protein sequence identity. In addition, when these six enzymes transfer fucose to 3'-sialylated or 2'-fucosylated Type I or Type II structures, they also exhibited distinct preferences (Supplementary Table I). Likewise, human FUT3 and FUT5 behave differently in terms of 1,4 specificity. FUT5 fucosylates H type I only on core 2 [Galß1,3(GlcNAcß1,6)GalNAc-Ser/Thr] structures, whereas FUT3 fucosylates H type I much more efficiently on core 3 (GlcNAcß1,3GalNAc-Ser/Thr) than core 2 structures (Holgersson and Lofling, 2006).
It is noteworthy that FUT4 and FUT7 are the only human FucT enzymes expressed in leukocytes, where they are responsible for generation of the functional selectin ligands (Homeister et al., 2001; Lowe, 2003). Sialyl-Lex is the core recognition epitope for E-, P-, and L-selectins that mediate not only the lymphocyte homing but also the initial leukocyte–endothelial cell adhesion events in both acute and chronic inflammation (Kannagi, 2002; Lowe, 2003). Production of Lex and sialyl-Lex by FUT4 and FUT7 in leukocytes is therefore crucial for leukocyte trafficking. In addition, Lewis-related carbohydrates are also involved in embryogenesis, angiogenesis, microbe-host interactions, neural development, fertilization, host-microbe interactions, and tumor metastasis (Norman et al., 1998; Ley, 2003). For instance, Lex is widely expressed on early embryonic cells and primordial germ cells in vertebrates (Muramatsu and Muramatsu, 2004). Sialyl-Lex/a expressed on capillary endothelial cells (Nguyen et al., 1992) participates in capillary morphogenesis through interaction with E-selectin (Nguyen et al., 1993). Ehrlichia equi- and Ehrlichia phagocytophila-related bacteria that cause human granulocytic ehrlichiosis contain selectin-like structures on their cell surface. As a consequence, through binding to P-selectin glycoprotein ligand-1 (containing sialyl-Lex moiety) expressed on leukocytes, bacteria display tropistic binding to host leukocytes (Herron et al., 2000). In addition, sialyl-Lex/a are heavily expressed on malignant cancer cells and are believed to interact with endothelial E-selectin to promote tumor progression and hematogenous metastasis, while cancer cells are also able to induce endothelial E-selectin expression (Kannagi, 2004). As a result, sialyl-Lex/a is not only a cancer marker but also a marker for cancer diagnosis and prognosis, such that higher levels of sialyl-Lex/a is correlated with increased metastasis and poor prognosis (Kannagi, 2004; Magnani, 2004).
1,4 Fucosylation in plants
Plant N-glycans are in the forms of oligomannosidic (Man>5GlcNAc2), paucimannosidic and complex types (Lerouge et al., 1998). The Lea moiety, localized at the antennae of N-glycans (Figure 2A), has been detected not only in Monocotyledons and Dicotyledons (Fitchette-Laine et al., 1997; Lerouge et al., 1998; Bakker et al., 2001; Wilson, 2001; Leonard et al., 2002, 2005; Castilho et al., 2005), but also in Physcomitrella patens (a monoecious moss) and various bryophyte species (Vietor et al., 2003). Indeed, the bryophyte species seem to contain similar types of N-glycans as those found in higher plants (Vietor et al., 2003).
Although Lea is expressed in all plant tissues (flowers, leaves, roots, and seedlings), the 1,4 FucT activity is predominant in young tissues (leaves and roots) (Lerouge et al., 1998). It appears that young growing tissues require de novo synthesis of Lea, which might play a role in cell elongation and/or differentiation. Moreover, peak 1,4 FucT activity is also detected in tobacco seeds, male flowers, and during tobacco male gametophyte development (pollen maturation, pollen germination, and tube elongation) (Joly et al., 2002), suggesting that Lea likely plays an important role in plant reproductive development. Additionally, plant 1,4 fucosylation is also suggested to be involved in cell-to-cell communication and/or recognition (Fitchette-Laine et al., 1997).
The FucT responsible for Lea production was isolated from Arabidopsis thaliana (Leonard et al., 2002) and sycamore cells (Fitchette-Laine et al., 1997) and was examined to have exclusive 1,4 activity. Based on the sequence alignment, these plant 1,4 FucTs contain the Trp residue (Bakker et al., 2001; Leonard et al., 2002) that confers the specificity of fucose transfer at 1,4 linkages for human FUT3 and FUT5 (Dupuy et al., 1999, 2004). Whether the Trp residue of plant 1,4 FucTs also confers Type I acceptor specificity awaits experimental examination.
1,3/4 Fucosylation in S. mansoni
One major feature of schistosomal glycoconjugates is that they are rich in fucose and GalNAc moieties but lack sialic acid. Human schistosomes (blood flukes) are digenic trematodes causing schistosomiasis, and they have several developmental stages. Schistosomal eggs firstly are discharged from the human host and enter the intermediate host (snails) where cercariae develop. Cercariae can penetrate human skin and enter the human bloodstream becoming the schistosomula, which develop into sexually mature adults after encountering a partner of the opposite sex (Cummings and Nyame, 1996). Fucosylated glycoconjugates are observed in all developmental stages; however, much higher levels of FucT activities were found in egg extracts in comparison with cercarial or adult worm extracts (Marques et al., 2001), suggesting that FucT activities are differentially regulated during development.
Schistosomal 1,3/4 FucTs are able to use both unsubstituted, 1,2-fucosylated and 2,3-sialylated Type II-structure, no matter whether these sugar moieties are in the form of oligosaccharides, glycoproteins, or glycolipids. Nevertheless, they use Type I series acceptor molecules much less efficiently (Hokke et al., 1998; Marques et al., 2001). Oligomeric Lex and polymeric Lex (n > 25) are detected not only on the O-linked glycans of gut-associated circulating cathodic antigen (van Dam et al., 1994; Cummings and Nyame, 1996) but also on N-glycans of schistosome eggs (Cummings and Nyame, 1996). Moreover, schistosomal glycoconjugates contain the fucose moiety linked to the GalNAc group within the LacdiNAc(GalNAcß1,4GlcNAc)-repeat structure forming Fuc1,3GalNAcß1,4GlcNAc (Wuhrer et al., 2006). Additionally, a pseudo Ley [Fuc1,3Galß1,4(Fuc1,3)GlcNAcß1-R] structure was found in cercarial extracts containing a Fuc1,3Gal linkage (Wuhrer et al., 2000; Hokke and Deelder, 2001). These data suggest that either schistosomal 1,3/4 FucTs have fairly loose acceptor specificity or some as yet unidentified FucT subfamilies with unique acceptor recognition are present and await discovery.
Notably, the first cloned schistosomal FucT gene was discovered to share identical nucleotide sequences with mouse fut7 gene except its 5' untranslated sequence and the first 39 translated base pairs (Smith et al., 1996; Marques et al., 1998). It has been proposed that a possible horizontal transfer of mouse DNA to the parasite might have occurred (Oriol et al., 1999), but such transmission remains to be examined closely.
In addition to being involved in many aspects of the parasite’s life cycle, schistosomal fucosylated glycoconjugates play a significant role in modifying the host’s immune responses (Cummings and Nyame, 1996, 1999). S. mansoni egg antigens and the glycolipids derived from cercariae and their excretory/secretory products have the ability to bind to dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) with high affinity (Appelmelk et al., 2003), and the binding ligands are Lex and pseudo-Ley [Fuc1,3Galß1,4(Fuc1,3)GlcNAcß1-R] determinants (van Die et al., 2003; Van Liempt et al., 2004; Meyer et al., 2005). Upon egg deposition in murine schistosomiasis, the Th1 response is down-regulated and the Th2-type response becomes predominant (Velupillai and Harn, 1994). Moreover, the oligosaccharide that contains trisaccharide Lex on both schistosome eggs and schistosomula caused proliferation of the spleen B cells and induced the production of interleukin-10 and prostaglandin E2, both of which are down-regulators of the Th1 cell response. The nature of the oligosaccharide interaction with B cells is currently unknown (Velupillai and Harn, 1994).
It has been shown that Lex repeats evoked high titres of specific immunoglobulin M (IgM) antibodies in S. mansoni-infected animals and humans (Ko et al., 1990; Srivatsan et al., 1992; van Dam et al., 1994). These antibodies are believed to cross-react with the repeating Lex structures expressed on the surface of granulocytes, leading to the lysis of granulocytes in the presence of complement (Nyame et al., 1996; van Dam et al., 1996). Furthermore, the LacdiNAc and fucosylated LacdiNAc repeats are also immunogenic and are involved in host–parasite interactions (Nyame et al., 1999, 2000).
1,3/4 Fucosylation in bacteria
Putative bacterial 1,3/4 FucTs have been identified in E. coli (Daniels et al., 1992), Vibrio cholerae (Stroeher et al., 1997), Rickettsia conorii (Ogata et al., 2000), Salmonella enterica serovar Typhi (McClelland et al., 2001; Parkhill, Dougan, et al., 2001), Yersinia pestis (Parkhill, Wren, et al., 2001), Yersinia pseudotuberculosis (Chain et al., 2004), and Mesorhizobium loti (Sullivan et al., 2002), but only 1,3/4 FucTs from H. pylori have been extensively characterized.
The H. pylori genome contains two paralogous genes futA and futB that encode two 1,3/4 FucTs, FutA and FutB, respectively (Berg et al., 1997; Alm et al., 1999). Similar to the futC gene, futA and futB also contain the polyA-polyC tract near the 5' end, and these poly-nucleotide tracts have a higher frequency of addition or deletion of one or more base pairs during DNA replication, leading to on/off status of the gene (Wang et al., 2000).
Unlike mammalian cells, difucosylated Lewis antigens (Ley and Leb) on H. pylori LPS are synthesized primarily through subterminal fucosylation (in 1,3 or 1,4 linkage) followed by terminal fucosylation (in 1,2 linkage) (Wang et al., 2000). Additionally, H. pylori 1,3/4 FucTs lack the N-terminal cytosolic tail and transmembrane domain that are present in mammalian counterparts; instead, they have a heptad-repeat region at the C-terminus, which is absent in mammalian enzymes (Ge et al., 1997; Martin et al., 1997; Rasko, Wang, Palcic, et al., 2000). 1,3/4 FucTs from different strains share >70% sequence identity, containing a highly conserved internal catalytic domain but a divergent N- and C- termini (Rasko, Wang, Palcic, et al., 2000). Most H. pylori 1,3/4 FucTs (i.e., from H. pylori strains NCTC11639 and NCTC11637) have exclusive 1,3 activity (Ge et al., 1997; Martin et al., 1997), but some (i.e., H. pylori strains UA948 and UA1111) possess both 1,3 and 1,4 activities (Rasko, Wang, Monteiro, et al., 2000; Rasko, Wang, Palcic, et al., 2000). 1,3/4 FucT from strain DMS6709 was recently reported to contain primarily 1,4 activity and only little 1,3 activity (Rabbani et al., 2005). Domain swapping and site-directed mutagenesis studies showed that the C-terminal hypervariable region (immediately upstream of the heptad-repeat region) (Ma et al., 2003), an aromatic residue (Tyr) in particular (Ma et al., 2005), of H. pylori 1,3/4FucT from strain UA948 is responsible for Type I acceptor recognition.
The functions of fucosylated carbohydrates on H. pylori LPS are not completely understood despite extensive investigation. As gastric mucosa secretes highly glycosylated molecules that contain Lewis blood group structures: Lea and Leb predominantly from the gastric surface epithelia and Lex and Ley primarily from the gastric deep glands (Cordon-Cardo et al., 1986; Kobayashi et al., 1993; Taylor et al., 1998; Lee, Choe, et al., 2006), molecular mimicry was therefore proposed to be a possible mechanism used by H. pylori to evade the immune response and thus maintain a long-term infection (Appelmelk et al., 1997). The same function has also been suggested for the sialyl-Lex expressed on the cell surface of some oral bacteria that are associated with infected endocarditis, such as Streptoccocus pyogenes, Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Eikenella corrodens (Hirota et al., 1995). The sialyl-Lex structures not only may camouflage these bacteria and aid them in traveling away from their normal habitats but also are involved in binding to endothelial selectins to initiate inflammation (Hirota et al., 1995).
It was proposed that H. pylori Lewis antigens may also induce production of auto-antibodies causing antigastric auto-reactivity leading to tissue damage (Wirth et al., 1997; Heneghan et al., 2001). Further evidence indicated that Lewis antigens were not the antigenic component (Faller et al., 1998; Yokota et al., 1998) but that a structure in the polysaccharide chain of LPS served that function (Yokota et al., 1998). The same conclusion had been made for Helicobacter mustelae that express the blood group antigen A structure on the LPS core region (Monteiro et al., 1997). Serum from H. mustelae-infected ferrets displayed no reaction with blood group antigen A or B, and the antibodies produced were not absorbed by red blood cells expressing blood group A or by H. mustelae whole cells (Monteiro et al., 1997). This suggests that Lewis blood group antigen structures on bacterial LPS are not the antigenic elements causing autoimmune responses.
Among fucosylated carbohydrate structures, Lex on H. pylori LPS was discovered to function as an adhesin involved in the tropistic binding of H. pylori to the apical surface of gastric mucosal epithelial cells and to cells of the gastric pits (Edwards et al., 2000). However, accumulating evidence supports the idea that Leb binding adhesin (BabA) in H. pylori plays the most significant role in the binding process (Ilver et al., 1998), whereas Lewis blood antigens on bacterial cell surface are not the prerequisite for H. pylori to colonize or to adhere. Lex-mediated binding, in fact, plays a minor role in both the processes and functions only in some but not all strains (Guruge et al., 1998; Suresh et al., 2000; Takata et al., 2002; Altman et al., 2003). A recent study confirmed that Lex-mediated adhesion is only significant when BabA–Leb binding is absent (Sheu et al., 2006). Nevertheless, the presence of fucosylated oligosaccharides on H. pylori LPS has been found to be correlated with the occurrence of more severe gastric diseases (Monteiro et al., 2001; Rasko et al., 2001; Eaton et al., 2004).
Recently, the Lewis blood antigens of H. pylori were discovered to interact with DC-SIGN expressed on dendritic cells to produce increased amount of interleukin-10 (Appelmelk et al., 2003; Bergman et al., 2004). Being a Th2 cytokine, interleukin-10 blocks the Th1 response and promotes Th2 activation, thus modulating the host immune response (Bergman et al., 2004). Surfactant protein D, a pathogen-associated molecular pattern recognition receptor, is also expressed on human gastric mucosa and plays a role in innate immunity (Madsen et al., 2000). The surfactant protein D has a low affinity for fucose but a high affinity for glucose and galactose (Madsen et al., 2000). Because H. pylori Lewis antigen expression is regulated by phase variation at the rate of 0.2–0.5% (Appelmelk et al., 1998), the levels of fucosylation, glucosylation, or galactosylation on H. pylori LPS fluctuate; so, binding affinity of H. pylori to surfactant D may also be modified leading to altered host immune response (Khamri et al., 2005). In summary, fucosylated structures on bacterial LPS, through molecular mimicry, enhancing adhesion and modulating host immune response, are believed to aid bacteria in adapting effectively to their niche to maintain a persistent infection.
Core 1,3 fucosylation
Some 1,3/4 FucTs can transfer fucose from GDP-Fuc to the innermost GlcNAc moiety of the chitobiose unit of the core Asn-linked glycans at an 1,3 linkage (Figure 2A). These enzymes, present in insects, plants, parasites, C. elegans, and Drosophila melanogaster but absent in mammals and bacteria (Staudacher et al., 1995; Fabini et al., 2001; Paschinger et al., 2005) are named core 1,3 FucTs, which also belong to CAZY family 10 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html).
One major feature of plant N-glycans is the presence of ß1,2-xylose and 1,3-fucose on the trimannosyl core region (Wilson and Altmann, 1998; van Die et al., 1999; Wilson et al., 2001; Leonard et al., 2004; Castilho et al., 2005). The core 1,3 FucT isolated from mung beans is capable of transferring fucose to the GlcNAc moiety at the reducing end of N-glycopeptides or related structures carrying GlcNAc2-Man3-GlcNAc2 (Staudacher et al., 1995). Similar to plants, schistosomal N-glycan also contains core 1,3-fucose and core ß1,2 xylose moieties, and these structures on egg-derived glycoproteins have been reported to induce strong Th2 cytokine responses and elicit production of IgG1 (a Th2-associated isotype) but not IgG2b (a Th1-associated isotype) antibodies in S. mansoni-infected C57BL/6 mice (Faveeuw et al., 2003).
Comparison of mammalian and H. pylori 1,3/4 FucTs
As both mammalian and H. pylori 1,3/4 FucTs have been well characterized, they are the best FucT representatives for inter-kingdom comparison. Alignment of the H. pylori 1,3/4 FucTs with their mammalian counterparts demonstrated that the significant homology is observed only in a very short region within the catalytic domain where the two 1,3/4 FucT motifs are localized (Ge et al., 1997; Martin et al., 1997); yet strikingly, these two enzyme families seem to share remarkable functional similarities.
First, H. pylori 1,3/4 FucTs lack both an N-terminal tail and a transmembrane domain. Instead, they contain a heptad-repeat region followed by two putative predicted amphipathic helices at the C-terminus (Ge et al., 1997; Martin et al., 1997; Rasko, Wang, Palcic, et al., 2000; Ma et al., 2003). The leucine-zipper-like motif in the heptad-repeat region was suggested to mediate dimer formation (Ge et al., 1997; Martin et al., 1997). Recent thermal denaturation studies of the carboxyl terminal truncated H. pylori FucTs confirmed that the heptad repeats facilitate protein folding thus help to maintain a stable protein structure, which is aligned with the dimer formation model (Lin et al., 2006). The amphipathic helices may act as membrane anchors with the hydrophobic face embedded in the membrane and the positive charges interacting with phospholipid headgroups (Ma et al., 2003) (Figure 3B). Accordingly, H. pylori and mammalian FucTs share similar domain architecture but with opposite topology (Figure 3). As a consequence, the Type I acceptor recognition site for both mammalian and H. pylori 1,3/4 FucTs has been localized in their hypervariable stem regions (Legault et al., 1995; Xu et al., 1996; Nguyen et al., 1998; Ma et al., 2003) and was determined by a single aromatic residue (Dupuy et al., 1999, 2004; Ma et al., 2005). In addition, the membrane anchor region (N-terminus of mammalian FucTs versus the C-terminal amphipathic helices of H. pylori enzymes) can be truncated without significantly diminishing the enzyme activity, whereas removal of one amino acid at the C-terminus of human FucT V or ten amino acids from N-terminus of H. pylori FucTs (from strains NCTC11639 and UA948) almost completely abolished enzyme activity (Xu et al., 1996; Ge et al., 1997; Lin et al., 2006; Ma et al., 2006).
Second, similar to mammalian 1,3/4 FucTs, the hydroxyl group at C-6 of galactose in Type I and Type II acceptors is essential for recognition by H. pylori 1,3/4 FucTs (de Vries et al., 1995; Du and Hindsgaul, 1996; Gosselin and Palcic, 1996; De Vries et al., 1997; Ma et al., 2006). Like human enzymes, H. pylori 1,3/4 FucTs were able to use both the sialylated Type I and sialylated Type II acceptors (de Vries et al., 1995; De Vries et al., 1997; Sherwood et al., 2002; Rabbani et al., 2005; Ma et al., 2006). Kinetic studies showed that H. pylori 1,3/4 FucTs possess kinetic parameters comparable to their mammalian counterparts (de Vries et al., 1995; De Vries et al., 1997; Nguyen et al., 1998; Rabbani et al., 2005; Ma et al., 2006). In addition, both human and H. pylori 1,3/4 FucTs seem to catalyze fucose transfer following a sequential mechanism, with binding of donor molecule first followed by the acceptor (Qiao et al., 1996; Ma et al., 2006). All these functional similarities indicate that mammalian and bacterial 1,3/4 FucTs very likely share a conserved mechanistic and structural basis for fucose transfer. Such striking inter-kingdom functional similarity might also be present in other FucT subfamilies but remains to be identified.
Recently, it was reported that the heptad-repeat number of H. pylori FutA and FutB protein is directly correlated with the size of O-antigen polymer being fucosylated (Nilsson et al., 2006). The authors proposed a model in which FutA and FutB formed heterodimers or homodimers in which the number of heptad repeats controls the distance of the active fucosylation site from a fixed point and thus determines the size of the O-antigen polymer that is fucosylated. Although this fixed point was not explicitly articulated in the study, it should reside in the bacterial inner membrane where both FucT enzymes and O-antigen polymer substrates are anchored. Our previous dynamic light scattering experiments verified that the FutA protein from H. pylori strain ACTC11639 forms a dimer (Ma et al., 2006), however two issues remain to be addressed. First, it is not yet known whether dimerization is essential for enzyme activity. If it were not, then the idea that the heptad-repeat number controls the size of fucosylated O-antigen polymer would be independent of dimerization. Second, there is still no evidence that FutA and FutB can form a heterodimer, and no data to indicate whether heterodimer formation is preferable to homodimer formation as suggested by Nilsson (2006). When the heptad-repeat number of FutA and FutB varies significantly, one would expect the heptad-repeat-mediated interaction between homodimers to be much stronger than that between heterodimers. Moreover, some H. pylori strains (i.e., NCTC11639 and UA948) only express one full-length functional FucT protein (either FutA or FutB) (Ge et al., 1997; Rasko, Wang, Palcic, et al., 2000) where merely homodimers can be formed.
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1,6 Fucosylation
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FucTs that add fucose to the innermost GlcNAc moiety of the chitobiose unit of the core Asn-linked glycans at an
1,6 linkage are designated 1,6 FucTs (Figures 1 and 2A) (Miyoshi et al., 1999; Yamaguchi et al., 1999, 2000). 1,6 FucTs show the highest activity in the presence of Mn2+, Mg2+, and Ca2+ but remain active when the metal cations are absent (Chazalet et al., 2001; Ihara et al., 2006). Recent kinetic studies supported that human 1,6 FucT adopts a rapid equilibrium random mechanism for fucose transfer (Ihara et al., 2006), in contrast to previous prediction of the ping-pong bi bi mechanism (Takahashi, Ikeda, Tateishi, et al., 2000). 1,6 FucTs are grouped into CAZY family 23 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html).
1,6 Fucosylation in mammals
The synthesis of the oligosaccharide precursor (Glc3Man9GlcNAc2) of N-glycans begins in the cytoplasm and is trimmed and assembled at the ER membrane on a dolichyl-pyrophosphate carrier by a series of ER-localized glycosidases and glycosyltransferases. 1,6 FucT, acting at late Golgi cisternae (Kornfeld and Kornfeld, 1985), requires an unsubstituted ß1,2-linked GlcNAc on the 1,3-mannose arm of the core N-glycans (Longmore and Schachter, 1982; Voynow et al., 1991; Uozumi et al., 1996).
Human 1,6 FucT, encoded by fut8, is widely expressed in mammalian tissues (Miyoshi et al., 1999; Yamaguchi et al., 1999, 2000). Two Arg residues, in motif I (see Sequence homology and structural prediction of FucT subfamilies) common to 1,2, 1,6 and O-FucTs, were shown to be involved in GDP-Fuc binding (Takahashi, Ikeda, Tateishi, et al., 2000). A recent study showed that the sugar moiety of GDP-Fuc did not contribute significantly to the binding and recognition by FUT8. Instead, the guanine nucleotide and diphosphate portions of GDP-Fuc are more important (Ihara et al., 2006).
1,6 Fucosylation in S. mansoni, insects, and C. elegans
The schistosomal egg glycoproteins contain non-fucosylated, 1,6-monofucosylated, core 1,3/1,6-difucosylated, and xylosylated/1,6-fucosylated forms of N-glycans, whereas the latter two forms of glycan are not characteristic for cercariae and adult worms (Khoo et al., 1997b, 2001; Faveeuw et al., 2003). The core 1,6 fucosylated diantennary N-glycan in schistosomal adult worms is composed of Hex3–4HexNAc6–12Fuc1–6 carrying dimers in the form of not only LacNAc (Type II) but also LacdiNAc (GalNAcß1,4GlcNAc) with or without fucose 1,3 linked to GlcNAc residues in the antennae (Wuhrer et al., 2006). Indeed, the presence of a significant amount of LacdiNAc structure is a unique feature of schistosomal glycoconjugates.
N-glycan core structure with double fucosylation at 1,6- and core 1,3-linkages, seemingly absent in vertebrates, is present not only in schistosomes (Khoo et al., 1997a,b, 2001) but also in C. elegans (Paschinger et al., 2005) and insects (i.e., Mamestra brassicae, honey bee and Drosophila) (Staudacher et al., 1991; Staudacher and Marz, 1998). The core 1,3 FucT of Drosophila prefers core 1,6-fucosylated glycans over the non-fucosylated forms (Fabini et al., 2001), and honeybee-venom-gland extracts exhibit the core 1,3 activity with monofucosylated (at 1,6 linkage) N-glycan acceptor (Staudacher et al., 1991). In contrast, 1,6FucT seems to be no longer functional, once the GlcNAc residue is modified by fucose addition at the 1,3 linkage. Therefore, a strict order of 1,6 fucosylation before core 1,3 fucosylation is followed to synthesize the difucosylated N-glycan core structure (Staudacher et al., 1991; Staudacher and Marz, 1998; Fabini et al., 2001; Paschinger et al., 2005).
1,6 Fucosylation in Rhizobium
1,6 FucTs that have been identified in many species from C. elegans to mammals (Uozumi et al., 1996; Miyoshi et al., 1997) also exist in various soil bacteria such as Bradyrhizobium japonicum, Azorhizobium caulinodans, Mesorhizobium loti, and Rhizobium loti (Stacey et al., 1994; Fellay et al., 1995; Mergaert et al., 1996; Olsthoorn et al., 1998). 1,6 FucT from Rhizobium species is encoded by the nodZ gene, and it transfers fucose from GDP-Fuc to the C6 of GlcNAc at the terminal reducing end of chitin oligosaccharides or lipo-chitoligosaccharides (Stacey et al., 1994; Fellay et al., 1995; Mergaert et al., 1996; Olsthoorn et al., 1998). NodZ prefers chitin oligosaccharides as acceptors, the penta- and hexasaccharide forms in particular (Quinto et al., 1997). Nevertheless, other acceptors that contain an unsubstituted GlcNAc residue at the reducing end were also acceptors of NodZ but with poor affinity, such as O-acetylchitin (or O-acetylated derivatives) oligosaccharides, lipo-chitoligosaccharide, Lex, and free pentasaccharide (Man3-GlcNAc2) core structure of N-glycans (Stacey et al., 1994). The in vitro studies on selectivities of NodZ using various acceptor molecules suggested that Rhizobium NodZ fucosylates chitin oligosaccharides before their acylation (Quinto et al., 1997).
Rhizobium lipo-chitoligosaccharide consists of 3–6 ß1,4-linked GlcNAc residues and a fatty acid group attached to the nitrogen of the non-reducing terminal residue. The nature of the fatty acetyl chain, the number of core GlcNAc residues, and the presence or absence of additional substitutions (i.e., fucose or arabinose moieties) on the N-glycans of Rhizobium species all account for the host specificity and nodulation efficiency (Olsthoorn et al., 1998). Nevertheless, the fucose moiety added by NodZ was the most specific determinant for nodulation.
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Xyloglucan 1,2 fucosylation
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Xyloglucan
1,2 FucT is a plant 1,2 FucT, which is able to transfer fucose to the Gal residue at the reducing end of xyloglycan at an 1,2 linkage (Figure 2B) (Perrin et al., 1999), and is categorized into CAZY family 37 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html). Kinetic studies showed that donor GDP-Fuc and acceptor xyloglucan associated with xyloglucan 1,2 FucT in a random order (Faik et al., 2000). In addition, this enzyme does not require divalent ions for catalysis (Faik et al., 2000).
Xyloglycan, a principal hemicellulose of dicotyledonous and non-graminaceous plants, is composed of a ß1,4-D-glucan backbone that carries the 1,6 xylose moieties on three consecutive glucose residues. The second and the third xylose within a "X-X-X-G" building block may bear a D-Gal in a ß1,2 linkage, and the second of Gal is usually extended by fucose in an 1,2 linkage by xyloglucan 1,2 FucTs (Figure 2B). The xyloglucan containing Fuc1,2Galß1,2Xyl structure has been detected in sycamore cells (Hisamatsu et al., 1991), Arabidopsis and rapeseed (Zablackis et al., 1995), apple fruit (Vincken et al., 1996), and developing nasturtium fruits (Desveaux et al., 1998).
Xyloglucan 1,2 FucT from Arabidopsis (Sarria et al., 2001) and pea epicotyl (Hanna et al., 1991; Maclachlan et al., 1992) has been characterized and named AtFUT1 and PsFUT1, respectively. AtFUT1 and PsFUT1 are Type II membrane proteins and share 62.3% protein sequence identity. Both enzymes are able to transfer fucose to the Gal residue closest to the reducing end of the repeating subunit on xyloglucan. In Arabidopsis, there are nine other genes, atfut2–10, encoding proteins AtFUT2–10 sharing 47–62% sequence identity to AtFUT1, but they fail to transfer fucose to xyloglucan (Sarria et al., 2001; Reiter, 2002). AtFUT11, 12, and 13 were predicted to have core 1,3 FucT activity, unknown specificity, and 1,4 FucT activity, respectively (http://bioweb.ucr.edu/Cellwall/family.pl?family_id=33). None of AtFUT1–13 actually belong to the same enzyme family as their corresponding mammalian counterparts (FUT1–13) but they were named in a very similar manner. This reflects the inconsistent nomenclature in the current literature.
The mur2 mutant with a single nucleotide change in the atfut1 gene lacked fucosylation in all tissue xyloglucans but grew normally (Vanzin et al., 2002), indicating that the 1,2 fucosylation of xyloglucan is not essential for plant growth. Similarly, a T-DNA insertion in the atfut1 locus also displayed normal growth (Perrin et al., 2003). In contrast, the mur1 mutant with a defect in de novo synthesis of GDP-Fuc was slightly dwarfed (Reiter et al., 1993; Bonin et al., 1997), showing that growth was affected adversely. Nevertheless, O-acetylation of Gal was considerably reduced in fucose-deficient mutants (atfut1, mur1, and mur2) and slightly increased in plants over-expressing atfut1, and the Fuc-Gal-Xyl side chains were more frequently acetylated than Gal-Xyl (Perrin et al., 2003). Accordingly, 1,2 fucosylation of xyloglucan seems to promote O-acetylation of Gal residue on xyloglucan.
Of note, some unusual fucose linkages were detected in plants. For instance, a fucose was linked to the O-2 position of -arabinofuranosyl residue at 1,2 linkage in the primary roots of 6-day-old radish (Raphanus sativus) seedlings (Misawa et al., 1996). Fucose was also detected in a Fuc1,4Rhaß structure of rhamno-galacturonan I and II structures and arabinogalactan proteins from Arabidopsis (Zablackis et al., 1995; Rayon et al., 1999). In addition, a fucose associated with galactosyluronic acid at a 1,4-linkage was also found from soybean and pectin (Fransen et al., 2000). Whether these fucose-linkages are catalyzed by plant 1,2 and 1,4 FucTs that would need to possess wide acceptor specificity or whether the reactions are carried out by as yet unidentified new FucT subfamilies is currently unknown. One needs to keep in mind that the function of nine AtFUT1 homologs (AtFUT2–10) and AtFUT11–13 are not defined, and possibly, they are the enzymes that catalyzed the unusual fucosylation.
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O-Fucosylation |
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It has been discovered that fucose can also be transferred directly to the hydroxyl group of Ser and Thr residues of glycoprotein acceptors that contain either the epidermal growth factor (EGF) (Wang and Spellman, 1998
; Wang et al., 2001; Shao and Haltiwanger, 2003) or the thrombospondin type repeat (TSR) (Luo, Koles, et al., 2006; Luo, Nita-Lazar, et al., 2006) sequences (Figure 2C). These reactions are carried out by O-FucTs called OFUT1 and OFUT2 that belong to CAZY families 65 and 68 (http://afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html), respectively. Human O-FUT1 and O-FUT2 (named POFUT1 and POFUT2) are encoded by fut12 and fut13 genes, respectively. EGF and TSR are small cysteine-knot motifs with six conserved cysteines that form three disulfide bonds in different patterns, C1-C3, C2-C4, C5-C6 in EGF repeats versus C1-C5, C2-C6 C3-C4 in TSR (Luo and Haltiwanger, 2005). The EGF motif is 40 amino acids long and contains a consensus sequence of C2X3–5S/TC3, whereas the TSR motif is 60 amino acids long and has consensus sequence of WX5C1X2/3S/TC2X2; S/T is the fucosylation site (Figure 2C) (Wang and Spellman, 1998; Wang et al., 2001; Loriol et al., 2006; Luo, Koles, et al., 2006; Luo, Nita-Lazar, et al., 2006).
Unlike the other FucT members, O-FUT1 and O-FUT2 are predominantly ER-localized soluble proteins (Luo and Haltiwanger, 2005; Okajima et al., 2005; Luo, Koles, et al., 2006). All O-FUT1 orthologs have been found to contain a conserved C-terminal tetrapeptide sequence (KDEL), which retains enzymes in the ER (Okajima et al., 2005). O-FUT2 proteins, in contrast, do not seem to contain a similar tetrapeptide sequence at their C-terminus; so, their ER-retention signal and mechanism remain to be defined. Both O-FUT1 and O-FUT2 enzymes only recognize the properly folded EGF- (Wang and Spellman, 1998) and TSR-repeat sequences (Luo, Nita-Lazar, et al., 2006).
The EGF-repeat sequence has been found in Notch, Notch ligands, urinary- and tissue-type plasminogen activators, and coagulation factors VII, IX, and VII (Okajima and Irvine, 2002; Okajima et al., 2003), whereas the TSR sequence is present in extracellular matrix proteins involved in cell–cell and cell–matrix interactions (de Fraipont et al., 2001; Luo, Koles, et al., 2006; Luo, Nita-Lazar et al., 2006). The O-fucose transferred to the EGF repeats by O-FUT1 can be further extended to a tetrasaccharide by three glycosyltransferases. Fringe, an O-fucose ß1,3-N-acetylglucosaminyltransferase, elongates O-fucose to form a disaccharide, which is further extended to a tetrasaccharide (Rampal et al., 2005). The O-fucose on TSRs, in constrast, is elongated with a glucose moiety to form a disaccharide by ß1,3-glucosyltransferase (Sato et al., 2006; Luo, Nita-Lazar, et al., 2006). Fringe enzymes and ß1,3-glucosyltransferase specifically recognize the O-fucose moiety linked to EGF- and TSR-like repeats, respectively, without cross-reaction (Luo, Nita-Lazar, et al., 2006).
Among pathways involved in O-fucosylation, the Notch signaling pathway involved in many developmental events is well characterized. Notch are transmembrane glycoproteins with the extracellular domain bearing 29–36 EGF-like repeats (Okajima et al., 2005). The binding of Notch ligands to the extracellular domain of Notch causes proteolytic cleavage, leading to the release of the Notch intracellular domain, which then translocates to the nucleus and interacts with transcriptional factors to activate the targeted developmental genes (Haines and Irvine, 2003; Okajima et al., 2003; Ahimou et al., 2004). Notch is synthesized in the rough ER as a single peptide precursor and transported to the cell surface (Okajima et al., 2003; Radtke and Raj, 2003) (Figure 4). Remarkably, both the ligand binding and the cell surface trafficking of Notch depend on O-fucosylation. It has been shown that when O-FUT1 was down-regulated by RNA interference in Drosophila or when the O-fut1 gene was mutated in Drosophila or in mouse, the Notch signaling pathway was not functional (Okajima and Irvine, 2002; Shi and Stanley, 2003). In wild-type Drosophila cells, Notch was predominantly expressed at the apical surface, but when O-FUT1 was down-regulated by RNA interference, Notch accumulated in the ER (Okajima et al., 2003). This is in contrast to other substrates of O-FUT1 whose localization remained unchanged. Moreover, when GMD was mutated, Notch was still detected on the cell surface and did not accumulate in the ER (Okajima et al., 2005). This suggests that O-FUT1 possesses a chaperone-like activity to control the trafficking of Notch from the ER to the cell surface. Nevertheless, Notch secretion does not seem to require FucT activity of O-FUT1 (Okajima and Irvine, 2002).
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Sequence homology and structural prediction of FucT subfamilies |
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To detect motifs common to
1,2, 1,3/4, and 1,6 FucTs, hydrophobic cluster analysis (HCA) was carried out to align FucTs from vertebrates, invertebrates, plants, and bacteria. HCA is an alignment method developed to detect distant evolutionary relationships by conservation of the hydrophobic clusters that define the hydrophobic core of globular proteins (Woodcock et al., 1992). HCA is efficient in capturing structural similarity beyond the very low primary sequence identity. Six FucT motifs were identified by using HCA analysis (Oriol et al., 1999): two in the catalytic region shared by 1,2 and 1,6 FucT families; two unique for 1,3/4 FucTs; one specific for 1,2 FucTs; and another specific for 1,6 FucTs (Oriol et al., 1999). Recently, a third motif common to 1,2 and 1,6 FucTs from both prokaryotic and eukaryotic origins was identified (Chazalet et al., 2001). Although 1,3 FucTs lack the consensus peptide segments shared by 1,2 and 1,6 FucTs, the first 1,3 FucT motif and the first 1,2/1,6 FucT motif seem to display some apparently similar hydrophobic features and conserved basic and acidic residues (Breton et al., 1996, 1998). HCA also demonstrated that bacterial 1,6 FucT (NodZ) and O-FUT1/2 contained three motifs common to 1,2 and 1,6 FucTs (Chazalet et al., 2001; Martinez-Duncker et al., 2003). Moreover, NodZ seems to share more similarities to plant 1,2 FucTs: two regions (a and b) at the N-terminal side of catalytic domain are conserved between NodZ and plant 1,2 FucTs (Chazalet et al., 2001). Phylogenic analysis has suggested that O-FUTs are more related to 1,6 FucTs than to 1,2 FucTs (Martinez-Duncker et al., 2003). Interestingly, plant xyloglucan 1,2 FucTs possess not only motif I that is common to 1,2 and 1,6 FucTs but also two short segments corresponding to motif III unique to 1,2 FucT and 1,6 FucT families, respectively (Faik et al., 2000). All these data suggest that 1,2, 1,6, O-FUTs, xyloglucan 1,2, and 1,3/4 FucTs are likely descended from a common ancestor, but 1,3/4 FucTs are more distant from the other subfamilies (Oriol et al., 1999; Chazalet et al., 2001).
To date, no crystal structure has been resolved for any member of the FucT family, although 3-D structures of dozens of glycosyltransferase superfamily members have been determined and thus provide an opportunity for predicting a fold for the FucT family. Despite great variation in protein sequences and donor/acceptor usages by a large number of glycosyltransferase members, this superfamily adopts a very limited number of folds, of which GT-A and GT-B are well characterized (Kelley et al., 2000; Unligil and Rini, 2000; Bourne and Henrissat, 2001; Kikuchi et al., 2003; Liu and Mushegian, 2003). Combining HCA and fold recognition, Breton and others (1996) proposed that 1,2 and 1,3 FucTs share the GT-B fold with ß-glucosyltransferase from bacteriophage T4 (BGT). The GT-B fold consists of two domains with an /ß/ structure forming a wide cleft where the donor and the acceptor bind (Lariviere et al., 2003). Likewise, Chazalet et al. (2001) utilized secondary structure and threading analysis to predict that bacterial 1,6 FucT (NodZ) contained a Rossman fold at the C-terminal part of the catalytic domain. They also predicted that 1,2, 1,3/4, and 1,6 FucTs all adopt a standard three layer /ß/ sandwich structure, with the BGT fold giving the highest score. Other studies based on PSI-BLAST search and structural analysis (Wrabl and Grishin, 2001; Liu and Mushegian, 2003) confirmed that 1,3/4 FucTs adopt a GT-B fold; however, 1,2 and 1,6 FucTs were predicted to adopt neither a GT-A nor a GT-B fold (Kikuchi et al., 2003). Additionally, taking the cysteine pairing pattern into consideration, de Vries, Knegtel, and others (2001) and de Vries, Yen and others (2001) have proposed a barrel fold for human FucT III and VII that is similar to tryptophan synthase from Salmonella typhimurium based on threading analysis. Unfortunately, the proposed barrel model itself was considered to be of low resolution and moreover containing some incorrect details (de Vries, Yen, et al., 2001). The barrel fold contains multiple ß-strand-loop--helix-turn units, and thus, remodeling analysis may have difficulty in distinguishing it from a /ß/ sandwich structure. Indeed, because almost no sequence homology is shared between FucTs and other glycosyltransferases with resolved 3-D structures, modeling studies are particularly difficult.
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Abnormal fucosylation in mammals |
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To date, at least 18 human genetic diseases result from altered protein N-glycosylation (Jaeken, 2003
; Marquardt and Denecke, 2003; Freeze and Aebi, 2005). As fucosylation is involved in many biological processes, abnormal fucosylation has also been observed in various disease states. In some situations, it is unambiguous that abnormal fucosylation leads to illness, whereas in many other ailments, it is hard to distinguish if abnormal fucosylation is a cause or a consequence of the disease. This section covers our current understanding of abnormal fucosylation in some diseases.
Defects in GDP-fucose transport to the Golgi
Leukocyte adhesion deficiency II (LAD II), which is categorized into the congenital disorder of glycosylation IIc (LAD II/CDG IIc), results from a defect in Golgi-localized Gft (Figure 4). Impairment is the result of either a single amino acid substitution to generate a dysfunctional transporter protein or truncation of a region required for both enzyme function and Golgi localization (Helmus et al., 2006). The leukocytes of LAD II patients lack expression of the selectin ligands Lex/a and sialyl-Lex/a on their surface. As a result, leukocytes in these patients are unable to adhere to E- and P-selectins on the surface of endothelial cells and thus fail to be recruited to inflammatory sites, leading to frequent recurrent infections. LAD II patients also display severe morphological and neurological abnormalities caused by unknown molecular mechanisms (Etzioni et al., 1992; Etzioni and Tonetti, 2000). It has been reported that some LAD II patients are responsive to exogenous fucose supplementation (Marquardt et al., 1999; Sturla et al., 2001; Wild et al., 2002; Hidalgo et al., 2003; Helmus et al., 2006), but how GDP-Fuc is transported into the Golgi in LAD II patients under the treatment condition is not yet understood. One possibility is that dysfunctional Gft possesses a much higher Km to GDP-Fuc than wild-type Gft; so, a sufficient amount of GDP-Fuc is required to assure a moderate transfer (Luhn et al., 2004).
LAD II patients display reduced fucosylation at 1,2, 1,3/4, and 1,6 linkages in their fibroblasts but little decrease in O-fucosylation (Sturla et al., 2003). Notably, core 1,6 fucosylation was diminished to the greatest extent, even though both expression and activities of 1,6 FucT were not significantly modified (Sturla et al., 2003, 2005). The reduction of core 1,6 fucosylation occurred mainly in the bi-antennary negatively charged N-linked oligosaccharides and was less pronounced in tri-antennary or in high mannose/hybrid oligosaccharides (Sturla et al., 2005). According to phenotype analysis of Drosophila Gft-defective mutants, Ishikawa and others (2005) reported that the Notch signaling pathway was also slightly affected by Gft defects in contrast to the drastic reduction in core 1,6 fucosylation. They therefore proposed that the reduced Notch signaling caused by Gft defects also contributes to the pathology of LAD II disease.
Two major hypotheses have been proposed to explain why O-fucosylation is least affected in Gft-defective mutants. First, O-FUTs possess a higher affinity for GDP-Fuc compared with 1,2, 1,3/4, and 1,6 FucTs (Wang et al., 2001). Second, unlike other FucTs, O-FUTs are localized in the ER (Luo and Haltiwanger, 2005), whereas GDP-Fuc is scarce in the Golgi apparatus when Gft is defective. This implies that another ER-localized Gft is present, which can import GDP-Fuc from the cytosol to the ER.
Defects in de novo synthesis of GDP-fucose
To determine the outcome when the de novo synthesis pathway of GDP-Fuc production is defective, mice were created with a mutation in FX protein (Figure 4). These mice exhibited a complete deficiency in cellular fucosylation, including N-fucosylation, O-fucosylation and E-/P-/L-selectin activities (Smith et al., 2002). FX–/– mice were infertile, their growth and development retarded, and they were defective in both leukocyte adhesion and homeostasis. Such a deficiency was reported to be reliably compensated by complementing with exogenous fucose to initiate the salvage pathway for GDP-Fuc synthesis (Smith et al., 2002).
Abnormal 1,2 fucosylation and diseases
To study the effects of 1,2 fucosylation on developmental processes, fut1 and fut2 null mice were created. These mice were viable and fertile, appeared healthy and developed normally (Domino et al., 2001), suggesting that 1,2 fucosylation is not indispensable for development. Nonetheless, the secretor status that is controlled by fut2 and controls the appearance of 1,2-linked fucose on oligosaccharides expressed on cell membrane, mucosa, and body fluids appears to influence susceptibility to some diseases. For instance, a positive association between blood group non-secretor phenotype and asthma has been reported in both a cohort of adult coal miners (Kauffmann et al., 1996) and children (Ronchetti et al., 2001), and the association in children was more significant in males (Ronchetti et al., 2001). In addition, HIV-infected patients have also been reported to be more often non-secretors, and the fucosylated but not galactosylated, glucosylated, lactosylated, or mannosylated bovine serum albumin was capable of inhibiting the binding between HIV and DC-SIGN-transduced Jurkat cells (Puissant et al., 2005). Therefore, it is proposed that the Leb antigen in secretors may have a slight protective effect by competing with HIV for binding DC-SIGN (Puissant et al., 2005), which is expressed on dendritic cells in mucosal tissues and has the ability of binding to HIV envelop protein gp120 through high-mannose-type N-glycans (Geijtenbeek et al., 2000). In contrast, other groups described the opposite findings: the non-secretor genotype was associated with reduced risk of HIV-1 infection (Blackwell et al., 1991; Ali et al., 2000; Puissant et al., 2005), and long-term non-progressive HIV patients were more often non-secretors in comparison to HIV-patients with acute disease progression and healthy blood donors (Kindberg et al., 2006). The precise relationship between secretor status and HIV infection as well as the underlining mechanism requires additional examination.
Abnormal 1,3 fucosylation and diseases
During inflammation and cancer, 1,3 fucosylation is often found to be increased (Mackiewicz and Mackiewicz, 1995), and such an increase is mainly observed in 1-acid glycoprotein (AGP) (Higai et al., 2003, 2005). AGP is a serum acute phase glycoprotein containing five potential Asn-linked glycosylation sites. The N-glycosylation of AGP may form bi-, tri-, and tetra-antennary structures, some of which are 1,3 fucosylated forming a sialyl-Lex structure (Yoshima et al., 1981). The MALDI-TOF MS analysis of AGP N-glycans in the sera of patients with acute and chronic inflammation showed that the level of 1,3 fucosylation in all bi-, tri-, and tetra-antennary N-glycan structures was significantly increased (Brinkman-van der Linden et al., 1998; Wild et al., 2002). For instance, increased 1,3 fucosylation of AGP was observed in patients with Type I diabetes mellitus and a direct correlation between 1,3 fucosylation level in AGP and urinary albumin secretion was found, suggesting that 1,3 fucosylation of AGP might be another marker for monitoring disease progress (Poland et al., 2001). In addition, enhanced 1,3 fucosylation of AGP was also reported in rheumatoid arthritis patients (Elliott et al., 1997; Ryden et al., 2002). Studies have shown that 1,3 fucosylation level of AGP not only affects the activity of collagenase-3 and influences collagen binding but also has an effect on fibrillogenesis in rheumatoid arthritis (Haston et al., 2002). The AGP in rheumatoid synovial fluid, compared to normal plasma AGP, seems not to be sufficient to prevent excessive cartilage destruction and thus exacerbates the disease process (Haston et al., 2003). Moreover, mRNA expression of FUT7 was up-regulated on T cells in the synovial fluid from juvenile idiopathic arthritis patients compared with T cells in peripheral blood, and the increase in FUT7 mRNA expression was associated with augmented binding of T cells to P-selectin. This suggests that increased FUT7 expression might play a role in enhanced homing of T cells in the inflamed synovium (De Benedetti et al., 2003).
In cystic fibrosis (CF) patients, 1,3 fucosylation and 1,6 fucosylation were greatly increased, whereas 1,2 fucosylation and sialylation were reduced in airway mucins, epithelial cells, and peripheral membrane glycoproteins of skin fibroblasts in comparison with that in non-CF patients (Scanlin et al., 1985; Wang et al., 1990; Scanlin and Glick, 1999; Lamblin et al., 2001; Rhim et al., 2001). Enzyme activities and mRNA expression levels of 1,3 FucTs (FUT3, 4, and 7), sialyltransferases, and 1,2 FucTs in the extracts of airway epithelial cells of CF patients, however, were comparable to those of non-CF patients (Glick et al., 2001; Stoykova et al., 2003). Many hypotheses have been proposed to explain such modified glycosylation in the absence of altered expression and activity of the corresponding enzymes (Rhim et al., 2001). The most plausible hypothesis is that alterations of the terminal glycosylation pattern on the airway epithelial cells are directly related to the presence of the wild-type and mutated transmembrane conductance regulator (CFTR) (Figure 4), which is a transmembrane glycoprotein with chloride channel activity and is believed to be responsible for sorting out the proper compartmentalization of terminal glycosyltransferases (i.e., FucTs and sialyltransferases) through the Golgi (Scanlin and Glick, 2000; Glick et al., 2001) (Figure 4). The most common mutation of CFTR is deletion 
F508 (Riordan et al., 1989). Under normal conditions, the 1,3 FucTs act subsequent to sialyltransferases and 1,2 FucTs. However, when CFTR is mutated, the compartmentalization of the terminal glycosyltransferases in the Golgi is disrupted so that the 1,3 FucTs are sorted into a position before the sialyltransferases and 1,2FucTs (Allan and Balch, 1999). As a consequence, the sialyltransferases and 1,2 FucTs may fail to recognize the substrates that were already 1,3/4-fucosylated, and both sialylation and 1,2 fucosylation processes are therefore bypassed (Rhim et al., 2001).
It is noteworthy that two major pathogens that attack CF patients, Pseudomonas aeruginosa and Haemophilus influenzae, produce a few fucose-binding adhesins that recognize 1,3-fucosylated asialoglycoconjugates expressed on the airway epithelial cells (Avichezer and Gilboa-Garber, 1987; Doig et al., 1989; Gilboa-Garber et al., 1994). The altered glycosylation, particularly the increased 1,3-fucosylation in CF patients, could potentially lead to an enhanced bacterial binding. The crystal structure of the fucose-binding lectin (PA-IIL) of P. aeruginosa was recently resolved in complex with fucose, and the structural data showed that PA-IIL forms a tetrameric structure coordinated with two calcium cations to mediate fucose binding (Mitchell, Houles, et al., 2002). The binding inhibition assay confirmed that Lea is the most potent ligand for PA-IIL, whereas Lex, sialyl-Lex, and D-mannose conferred much weaker binding to PA-IIL (Mitchell, Houles, et al., 2002).
Abnormal 1,6 fucosylation and diseases
FUT8 is the only enzyme responsible for adding fucose to the Asn-linked GlcNAc moiety at 1,6-linkages on the core structure of N-glycans. To examine the consequences of void 1,6-fucosylation, fut8–/– null mice were created. It was shown that these mice either died during postnatal development or those that survived exhibited emphysema-like progressive changes in the lungs and retarded growth. Biochemical studies of the lungs in fut8–/– mice demonstrated over-expression of matrix metalloproteinases and reduced expression of extracellular matrix proteins (i.e., elastin) (Wang et al., 2005). Such changes resulted from the deficiency in the transformation growth factor ß1 (TGF-ß1) signaling pathway, which was responsible for inducing the expression of the extracellular matrix by down-regulating matrix metalloproteinase expression (Massague et al., 2000). Reintroduction of the fut8 gene into the fut8–/– mice successfully restored TGF-ß1 receptor binding, and the complementation of exogenous TGF-ß1 rescued both emphysema-like lung changes and the overexpression of matrix metalloproteinases. Therefore, core 1,6 fucosylation of TGF-ß1 receptor is crucial for proper function of TGF-ß1 signaling in the lung.
The extracellular domain of the EGF receptor contains 12 N-glycosylation sites. N-glycosylation inhibitors were able to dramatically decrease the binding of EGF to its receptor, suggesting that N-glycosylation is essential for ligand binding. Indeed, the EGF signaling pathway was disrupted in the embryonic fibroblasts of fut8–/– mice in comparison to fut8+/+ cells. The disruption was reflected in both EGF-induced phosphorylation and EGF receptor (EGFR)-mediated downstream c-Jun N-terminal Kinase (JNK) and Extracellular signal-Regulated Kinase (ERK) activation (Wang, Gu, et al., 2006). The expression levels of EGFR and the total activities of tyrosine phosphatase for phosphorylated EGFR, however, were comparable between fut8–/– and fut8+/+ cells (Wang, Gu, et al., 2006). When the fut8 gene was reintroduced to the fucT8–/– cells, the inhibition of EGFR was eliminated. In short, 1,6 core fucosylation seems essential for both TGF-ß1 and EGF signaling pathways, both of which mediate cell growth and cell differentiation.
FUT8 is abundantly expressed in liver, and the expression was greatly enhanced during chronic liver diseases and hepatocellular carcinoma. In fact, -fetoprotein, a well-known tumor marker has been observed to be extensively fucosylated by FUT8 in hepatocellular carcinoma (Noda, Miyoshi, et al., 1998; Noda, Miyoshi, et al., 1998; Noda et al., 2003). A recent study suggested that the fucosylation might act as sorting signal for secretion of glycoproteins into bile ducts in the liver (Nakagawa et al., 2006) In addition, the fucosylated haptoglobin was also observed more frequently at the advanced stage of pancreatic cancer (Okuyama et al., 2006), and both mRNA and protein expression levels of 1,6FucT and its activity were higher in human ovarian serous adenocarcinoma than in normal tissues (Takahashi, Ikeda, Miyoshi, et al., 2000). A recent study showed that loss of core fucosylation in fut8–/– mice also impaired the function of low-density lipoprotein receptor-related protein 1, which is a multifunctional scavenger and signaling receptor involved in the endocytosis of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3). In fut8–/– mice, the endocytosis of IGFBP-3 was reduced, whereas the serum level was increased, but the reduced endocytosis was restored by reintroduction of fut8, suggesting that core fucosylation is also crucial for the scavenging activity of LRP-1 in vivo (Lee, Takahashi, et al., 2006).
Abnormal O-fucosylation and diseases
The necessity of O-fucosylation has been well studied in the Notch signaling pathway, which is indispensable for the early development of C. elegans and Drosophila (Haltiwanger and Lowe, 2004; Shi et al., 2005) and is involved in many key events during embryonic development in mice and humans (Artavanis-Tsakonas et al., 1999; Weinmaster and Kintner, 2003) after gastrulation (Shi et al., 2005). O-fut1–/– mouse embryos died at midgestation and were defective in somitogenesis, vasculogenesis, cardiogenesis, and neurogenesis, similar to the phenotype where all Notch signaling pathway were blocked (Shi and Stanley, 2003). Recent studies demonstrated that Notch signaling was also required for mammary gland development in mice during pregnancy (Buono et al., 2006) and played an important role in proliferation and differentiation of normal prostatic epithelial cells (Wang, Leow, et al., 2006).
O-FUT2 orthologs have been found in various species from C. elegans to human. O-FUT2 is crucial for development in C. elegans (Menzel et al., 2004). The TSR proteins that were modified by O-FUT2 are involved in cell adhesion, neural development (Adams and Tucker, 2000), and tumor angiogenesis (de Fraipont et al., 2001). Our understanding of O-fucosylation is still in its infancy and the functional properties of O-fucosylation in the context of diseases await further studies.
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Application of FucTs, fucosylated oligosaccharides and FucT inhibitors |
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As fucose-containing carbohydrates are important in many biological processes (Boren et al., 1993
; Ilver et al., 1998; Taylor et al., 1998; Barchi, 2000; Mahdavi et al., 2003; Lerrer et al., 2005; Marionneau et al., 2005; Norman and Kubes, 2005; Thorven et al., 2005), FucTs show promise in the synthesis of carbohydrate drugs and optimizing oligosaccharide structures found on the surface of therapeutic glycoproteins. In addition, fut DNA sequences may be manipulated to alter carbohydrate structure found on the surface of cancer cells. Lastly, FucT inhibitors have potential in down-regulating FucT activity in vivo and thus inhibiting unfavorable biological processes involving fucose-containing carbohydrates.
Use of fucosyltransferases in the synthesis of fucosylated oligosaccharides and their applications in treatment
Enzymes may be used in the synthesis of oligosaccharides, however, there are four others sources of oligosaccharides. These include purification from natural or recombinant sources, chemical synthesis, and a combination of chemical and enzymatic synthesis. Purification of carbohydrates from natural sources is extremely difficult and costly (Allen et al., 2001; Seeberger, 2003); however, genetic modification of organisms to include the genes for important glycosyltransferases allows easier purification of oligosaccharides from these recombinant systems. As such, these whole cells may be considered "living factories" where the oligosaccharides of interest are found in higher amounts than normal and sometimes in an organism that would not normally produce the carbohydrate (Lubineau et al., 1998; Endo and Koizumi, 2000; Hamilton et al., 2003; Dumon et al., 2004; Salo et al., 2005; Drouillard et al., 2006). Unfortunately chemical synthesis of carbohydrates requires technically complex time-consuming reactions involving complicated protection and deprotection of reactive groups (Seeberger, 2003). Dispite this, one advantage of chemical synthesis is that non-natural oligosaccharides may be produced. Recent developments in chemical synthesis include the use of thioglycoside carbohydrate building blocks with varying reactivity in conjunction with computer aid to allow reactions to be carried out by mixing all reactants in one vessel (Burkhart et al., 2001; Mong and Wong, 2002) and automated solid-phase carbohydrate synthesizers (Plante et al., 2001, 2003; Seeberger, 2003; Seeberger and Werz, 2005) with capping techniques to aid in purification of complete oligosaccharides (Palmacci et al., 2001; Plante and Seeberger, 2003). It is hoped that, in the future, these two chemical platforms will become accessible to the non-expert. Nonetheless, enzymatic synthesis of carbohydrates continues to meet the requirements of stereo- and regioselective reactions with no side products being produced. In addition, only enzymes are useful in the modification of carbohydrate found on pre-existing protein.
FucTs are useful in the enzymatic synthesis of many fucose-containing molecules. The genes for FucTs have been used to produce recombinant organisms that now synthesize carbohydrates of interest that may be purified (Lubineau et al., 1998; Endo and Koizumi, 2000; Hamilton et al., 2003; Dumon et al., 2004; Salo et al., 2005; Drouillard et al., 2006). Alternatively, synthesis of carbohydrate may be performed in vitro (Lin et al., 1995), sometimes along with other glycosyltransferases and using sugar nucleotide regeneration systems (Ichikawa et al., 1992; Chen et al., 2001). In addition, FucTs may be used in chemoenzymatic synthesis (Ichikawa et al., 1992; Nelson et al., 1993; DeFrees et al., 1995; Renkonen et al., 1997; Koeller and Wong, 2000; Zeng and Uzawa, 2005; Malleron et al., 2006). FucTs are particularly useful in carbohydrate synthesis, as they tolerate significant alterations to acceptor molecules (Ohrlein, 2001). FucTs have been used in the synthesis of many molecules including blood group antigens (Ichikawa et al., 1992; Chen et al., 2001; Rabbani et al., 2005) that are important in metastasis of cancer cells (Barchi, 2000), inflammation (Norman and Kubes, 2005), bacterial adhesion (Boren et al., 1993; Ilver et al., 1998; Taylor et al., 1998; Mahdavi et al., 2003; Lerrer et al., 2005; Marionneau et al., 2005; Thorven et al., 2005), and self-recognition (Holgersson et al., 2005; Rydberg et al., 2005).
Fucosylated oligosaccharides in the inhibition of selectin-mediated interactions
Interactions between selectins and sialyl-Lex play an important role in many biological processes including cancer metastasis (Barchi, 2000) and leukocyte recruitment (Vanderslice et al., 2004). Although leukocyte homing is important in the inflammatory response, unnecessary or excessive leukocyte recruitment may result in reperfusion injury, asthma, and chronic obstructive pulmonary disease (Vanderslice et al., 2004). The inflammatory response is initiated by binding of sialyl-Lex on glycoproteins to selectins resulting in leukocyte rolling; therefore, interference with leukocyte rolling is expected to abrogate an excessive inflammatory response (Vanderslice et al., 2004).
Molecules containing sialyl-Lex and its mimetics have been examined for their use as therapeutics to down-regulate the inflammatory response in reperfusion injury, asthma, and chronic obstructive pulmonary disease (Romano, 2005). For instance, cylexin, a molecule with structural similarity to sialyl-Lex, was used in phase I and II clinical trials for the treatment of reperfusion injury in infants after heart surgery (http://www.clinicaltrials.gov/ct/show/NCT00226369?order=1). Unfortunately, the trial was discontinued because of poor results (Thompson, 1999). Additionally, administration of cylexin on the day of pulmonary thromboendartectomy surgery was shown to reduce the incidence of reperfusion lung injury (Kerr et al., 2000). Another selectin-binding molecule, P-selectin glycoprotein ligand with surface-exposed sialyl-Lex, is currently being evaluated in Phase I and II clinical trials as a therapeutic agent for the prevention of reperfusion injury after kidney transplantation (http://www.clinicaltrials.gov/ct/show/NCT00298168?order=18). Moreover, a sialyl dimeric Lex mimetic, Bimosiamose (Bimo-TCB1269) (Kogan et al., 1998; Michail et al., 2005; Beeh et al., 2006) is in phase II clinical trials for the treatment of asthma (Avila et al., 2004; www.revotar.de/product_pipeline.php), and phase I clinical trials for the treatment of chronic obstructive pulmonary disease (www.revotar.de/product_pipeline.php). As selectin-mediated interactions are involved in many biological processes, it is possible that long-term inhibition of these interactions could result in significant side effects in patients, but short-term inhibition should be well tolerated, such as would be needed in the treatment of reperfusion injury. Although the treatment of asthma with selectin inhibitors would require long-term inhibition of the inflammatory response, medication could be taken by aerosols and thus may be tolerated as systemic application of the drug is not required.
Fucosylated oligosaccharides in the inhibition of microbial adhesion
Antiadhesion therapy has been suggested for the treatment or prevention of microbial diseases, because many parasites, bacteria, and viruses are known to bind to carbohydrate structures in their efforts to initiate the infection process (Osborn et al., 2004). For instance, P. aeruginosa adhere to Lewis blood antigens (Lea, Lex, and sialyl-Lex) (Avichezer and Gilboa-Garber, 1987; Doig et al., 1989; Gilboa-Garber et al., 1994; Mitchell, Houles, et al., 2002; Lerrer et al., 2005), many Noroviruses require binding to H type 1 in secretor-positive hosts (Marionneau et al., 2005; Thorven et al., 2005), and H. pylori are known to bind to Leb (Boren et al., 1993; Ilver et al., 1998), sialyl-Lex (Mahdavi et al., 2003), and Lex (Taylor et al., 1998; Edwards et al., 2000) on the surface of the gastric epithelium. As a result, antiadhesion therapy using molecules with these fucose-containing carbohydrates has been suggested as an alternative to antibiotics for the eradiation of pathogenic organisms (Ofek and Sharon, 2002; Ofek et al., 2003; Sharon, 2006).
Pig milk proteins, containing Leb and sialyl-Lex, are able to inhibit binding of H. pylori to these same carbohydrate structures, as well as colonization in a mouse model system (Gustafsson et al., 2005). Polyvalency of therapeutic carbohydrate molecules may be required to achieve an affinity between the carbohydrate and the adhesin that is high enough to block the physiologically relevant interaction in vivo (Bovin et al., 2004; Osborn et al., 2004). Additionally, pathogens important in lung infection in CF patients, P. aeruginosa and H. influenzae, use asialofucosylated proteins as ligands for primary adhesion (Rhim et al., 2001; Stoykova et al., 2003). Although still to be explored, it is possible that a form of sialyl-Lex may be useful as an antiadhesin inhalant in these patients. Moreover, one study has found a correlation between HIV infection and a reduced frequency of the Lea–b+ phenotype (Puissant et al., 2005). Although there are studies that disagree with this finding (Ali et al., 2000; Kindberg et al., 2006), if Leb were confirmed to be able to compete with HIV envelope protein gp120 for DC-SIGN, Leb-containing molecules might also be considered in prevention or treatment of this disease.
Preventative antiadhesion therapy occurs in nature. Human breast milk contains upwards of 900 different fucosylated oligosaccharides that are believed to be important in protecting nursing infants from various infections (Newburg, 1997; Chaturvedi et al., 2001; Newburg et al., 2005), including those caused by E. coli stable toxin (Newburg et al., 1990, 2004), Campylobacter (Ruiz-Palicios et al., 2003; Morrow et al., 2004; Newburg et al., 2004), and norovirus (Jiang et al., 2004; Newburg et al., 2004). As a result, there is hope that antiadhesion therapy in the treatment of infectious disease will be effective, and FucTs may be used in the synthesis of fucosylated carbohydrates. Alternatively, FucT genes may be incorporated into harmless bacteria allowing these recombinant organisms to produce fucosylated LPS and be used as probiotics (Paton et al., 2006).
Fucosylated oligosaccharides as immunoadsorbants in transplantation therapy
Because of organ shortages, occasionally, the boundaries of ABO blood group compatibility are crossed during transplantation, particularly in the case of live donors. Under such circumstances, incompatible blood group antigen antibodies are best removed from the patient’s blood before transplantation of ABO-incompatible tissue (Holgersson et al., 2005; Rydberg et al., 2005), and FucTs may be used to produce blood group antigens. When these antigens are attached to column matrix, they act as binding ligands for blood group antigen antibodies (Holgersson et al., 2005; Rydberg et al., 2005). As a result, these columns may be successfully used to remove antibodies from a patient’s blood before ABO-incompatible transplantation.
Fucosylated oligosaccharides in cancer vaccines
The fucose-containing blood group antigens fucosyl GM1 (Dickler et al., 1999), sialyl-Lex (Menard et al., 1983), and sialyl-Ley (Kudrashov et al., 2001) are present on the surface of various types of cancer cells. As a result, FucTs may be used in the synthesis of these fucose-containing molecules for cancer vaccines. For instance, fucosyl GM1 has been used as part of a vaccine for small cell lung cancer (Allen and Danishefsky, 1999; Dickler et al., 1999; Krug et al., 2004), and sialyl-Ley has been used as part of a vaccine in Phase I clinical trials in patients with high risk of breast cancer recurrence (http://www.clinicaltrials.gov/ct/show/NCT00030823?order=2) or ovarian cancer (Sabbatini et al., 2000) and in phase II clinical trials for the treatment of prostate cancer (http://www.clinicaltrials.gov/ct/show/NCT00016120?order=1). Potential vaccines often possess multiple antigens on a single backbone (Slovin et al., 2005).
Glycoprotein remodeling
Many therapeutic agents, including monoclonal antibodies and cytokines, are glycoprotein drugs, and these are produced with less than favorable glycosylation patterns in recombinant expression systems (Thomas et al., 2004). As proteins with the correct glycosylation pattern may show increased bioactivity, stability, and decreased antigenicity, they are often approved more easily by the FDA. As a result, attempts have been made to improve glycosylation patterns on glycoprotein drugs. This includes alteration of recombinant expression systems by inserting or deleting the genes for the enzymes involved in glycosylation (Hamilton et al., 2003) or using glycosyltransferases in vitro (Witte et al., 1997; Hodoniczky et al., 2005). FucTs are therefore one of the enzyme families used in remodeling carbohydrate structures on the surface of therapeutic glycoproteins. For example, FUT6 and 2,3 sialyltransferase were used in vitro to remodel recombinant soluble human complement receptor type 1, a protein involved in the complement cascade. This increased both fucosylation and sialylation on the protein as well as E-selectin binding and pharmokinetics (Thomas et al., 2004).
Fucosyltransferases in gene therapy
Interactions between sialyl-Lex on the surface of cancer cells and selectins on endothelial cells have been shown to be important in cancer metastasis (Barchi, 2000). In addition to the use of sialyl-Lex and its mimetics, interference of selectin-mediated interactions can be achieved by fut genes to modify (Mathieu et al., 2004) or prevent the formation (Weston et al., 1999) of sialyl-Lex on the surface of cancer cells. In one study, tissue culture cells were transfected with fut1 changing carbohydrate structure on the surface of cells from Lex and Lea to Ley and Leb, leading to a concomitant decrease in E-selectin binding (Mathieu et al., 2004). In another study, a metastatic tissue culture cell line was transfected with antisense fut3. The transfected cell line no longer produced fut3 RNA, sialyl-Lex, or sialyl-Lea and was unable to metastasize to the liver in nude mice (Weston et al., 1999). It will be interesting to see if human therapeutics involving fut genes will be forthcoming.
Therapeutic potential of fucosyltransferase inhibitors
FucT inhibitors may also be useful as therapeutics for preventing formation of fucose-containing carbohydrates and thus preventing unfavorable protein carbohydrate interactions (Compain and Martin, 2001). Unfortunately, the lack of structural data for FucTs, as well as tolerance of these enzymes to different acceptor structures, has made inhibitor design particularly difficult (Ohrlein, 2001). Nonetheless, many inhibitors have been isolated from natural sources (Wakimoto et al., 1999; Niu et al., 2004; Lin et al., 2005) or synthesized chemically (Hindsgaul et al., 1991; Compain and Martin, 2001; Mitchell, Tian, et al., 2002; Lee et al., 2003; Bryan et al., 2004; Galan et al., 2004; Norris et al., 2004; Izumi et al., 2006), and their ability to inhbit FucTs has been examined. In general, FucT inhibitors resemble the donor (Kaminska et al., 1999; Norris et al., 2004), acceptor, or transition state molecule (Schuster and Belchert, 2001; Mitchell, Tian, et al., 2002). To date, the effects of most FucT inhibitors on sialyl-Lex production and accompanying selectin-mediated interactions have only been studied in a few cases (Kogan et al., 1995; Shinoda et al., 1998). For example, two FUT7 inhibitors, panosialin A and B, were found to decrease selectin-mediated interactions in a cell culture system (Shinoda et al., 1998). As described earlier, increased T-cell homing has been suggested to occur in rheumatoid arthritis because of increased expression of FUT7 and sialyl-Lex on the surface of T-cells (De Benedetti et al., 2003). In addition, the microbial pathogens P. aeruginosa and H. influenza appear to bind more easily to lung tissues in CF patients as the patients show increased 1,3 fucosylation on membrane glycoproteins (Glick et al., 2001). Consequently, it is worth considering that panosialins A and B, or other FucT inhibitors, may be useful in treatment of arthritis or in the prevention or treatment of microbial infections in CF patients. Nonetheless, the side effects of the systemic use of FucT inhibitors may be substantial considering sialyl-Lex selectin-mediated interactions are important in so many biological processes.
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Concluding remarks |
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Fucosylation, present in both eukaroytic and prokaryotic organisms, is crucial for many biological processes from C. elegans to mammals and the fucosylated carbohydrate structures expressed on the outer membrane of microbes play an important role in bacterial pathogenesis through interacting with the human host. Investigation of the enzymatic properties of FucTs has established a concrete foundation for understanding the fucosylation process. Furthermore, analysis of the abnormal fucosylation that occurs in many diseases not only provides invaluable insight into deciphering the mechanisms of the diseases but also aids in seeking out new means for treatment.
Despite the significant progress in understanding the various fucosylation processes made in the past decade, many areas related to fucosylation are presently unknown. For instance, 1,3/4 FucTs from mammals and H. pylori are the only FucT enzymes whose structure–function relationship has been extensively examined, whereas the enzymatic properties of other FucTs (1,2 FucTs, 1,6FucTs, O-FUT1/2, and xyloglucan 1,2 FucT) are largely undefined. Moreover, FucTs present in plants and S. mansoni that display unusual acceptor specificities remain to be characterized and additional FucT subfamilies might exist. In addition, our understanding of the function of fucosylation in each organism is still fairly limited. For instance, although the Notch pathway has been investigated extensively, no data are yet available on the significance of fucosylated TSR proteins. Moreover, it is not yet known why schistosomes are heavily fucosylated but lack sialylation and why C. elegans contains many FucT homologs. Paradoxically, although dozens of enzymes that belong to the glycosyltransferase superfamily have resolved crystal structures (Breton et al., 2005; Qasba et al., 2005), no member of any FucT family has yet been reported to form a crystal. Continued studies on fucosylation and FucT enzymes will greatly advance our understanding of many biological and pathological processes in different organisms. In addition, new knowledge would also boost the potential application of FucTs in enzymatic synthesis of oligosaccharides and glycoconjugates and accelerate the progression of developing more efficient treatments for many diseases.
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Supplementary Data |
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Supplementary data are available at Glycobiology online (http://glycob.oxfordjournals.org/).
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Acknowledgments |
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We greatly appreciate Dr. Bart Hazes and Dr. Mario Feldman for critical reading of the manuscript. D.E.T. was supported by an Alberta Heritage Foundation for Medical Research Senior Investigator Award.
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Conflict of interest statement |
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None declared.
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Abbreviations |
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AGP,
1-acid glycoprotein; BabA, Leb binding adhesin; BGT, ß-glucosyltransferase from bacteriophage T4; CAZY, Carbohydrate-Active enZYmes; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; DC-SIGN, dendritic cell-specific ICAM-grabbing non-integrin; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERK, Extracellular signal-Regulated Kinase; FucTs, fucosyltransferases; FX, GDP-keto-6-deoxymannaose 3,5-epimerase/4-reductase; GDP-Fuc, guanosine-diphosphate fucose; Gft, guanosine-diphosphate fucose transporter; GMD, guanosine-diphosphate fucose-mannose 4,6-dehydrase; HCA, hydrophobic cluster analysis; IGFBP-3, insulin-like growth factor-binding protein-3; JNK, c-Jun N-terminal Kinase; LAD II, leukocyte adhesion deficiency II; LPS, lipopolysaccharide; TGF-ß1, transformation growth factor-ß1; TSR, thrombospondin type repeat; Type I, Galß1,3GlcNAc; Type II (LacNAc), Galß1,4GlcNAc; Type III, Galß1,3GalNAc |
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