Glycobiology vol. 16 no. 12 pp. 158R–184R, 2006
doi:10.1093/glycob/cwl040
Advance Access publication on September 14, 2006
REVIEW
Fucosylation in prokaryotes and eukaryotes
Bing Ma, Joanne L. Simala-Grant, and Diane E. Taylor1
Department of Medical Microbiology and Immunology, University of
Alberta, Edmonton, Alberta, Canada T6G 2H7
Received on June 21, 2006; revised on August 25, 2006; accepted on
August 25, 2006
Fucosylated 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 a1,3/4 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
Introduction
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).
1
To whom correspondence should be addressed; e-mail:
[email protected]
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 α1,2, α1,3/4, α1,6, 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 nonGolgi α1,2 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 α1,2 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).
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 GDPmannose to GDP-Fuc via GDP-mannose 4,6-dehydrase
(GMD) and GDP-keto-6-deoxymannaose 3,5-epimerase/4reductase (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
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Fucosylation in prokaryotes and eukaryotes
a1,2 Fucosylation in mammals, Caenorhabditis elegans and
Schistosoma mansoni
Fig. 1. Fucosylation sites of human α1,2, α1,3/4, and α1,6 FucTs. Both of
the two main types of acceptor substrates, O-glycans (left) and N-glycans
(right), contain poly-LacNAc chains (in brackets), but chitobiose (grey
square) is only found in N-glycans. Fucosylation sites of human α1,2 and
α1,6 FucTs are shown on the antennae of O- and N-glycans. For human
α1,3/4 FucTs, only their preferred fucosylation sites are given, even
though they are able to add fucose to either internal, middle, or distal sites
of GlcNAc in poly-LacNAc chains. Of note, FUT7 cannot use Type II
acceptor unless it is sialylated (in light gray shade). With the sialylatedType II acceptor, FUT9 switches the preferred fucosylation site from distal to the inner most GlcNAc (in light gray shade). The black and the dark
gray blocks at the bottom represent proteins. Asn, asparagine; Gal, galactose; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine;
Man, mannose; Neu5Ac, sialic acid; Ser, serine; Thr, threonine.
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 ERlocalized Gft, which has not yet been identified.
a1,2 Fucosylation
α1,2 FucTs transfer fucose at an α1,2 linkage from GDPFuc to the galactose moiety of Galβ1,4GlcNAc (Type II,
also called LacNAc) or Galβ1,3GlcNAc (Type I) structures, which are localized at the peripheral (antennae)
position of acceptor molecules (Figures 1 and 5). α1,2
FucTs, belonging to CAZY family 11 (http://afmb.cnrsmrs.fr/CAZY/fam/acc_GT.html), were shown to adopt
random bi bi mechanism for fucose transfer (Palcic et al.,
1989).
In the human genome, fut1, fut2, and sec1 (a pseudogene
with a mutation causing a frameshift) encode the H, Se
(secretor), and non-functional α1,2 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) α1,2 FucTs show different acceptor specificities;
the former prefers Type I and Type II acceptors and is less
efficient in fucose transfer to Galβ1,3GalNAc (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 α1,2 FucTs from
C. elegans, one of them, CE2FT-1, prefers the unusual sugars Galβ1,4Xyl-R and Galβ1,6GlcNAc-R as acceptors.
CE2FT-1 is expressed in all developmental stages of
C. elegans and shares only 5–10% sequence identity to α1,2
FucTs from human, rabbits, and mice (Zheng et al., 2002).
It is unable to fucosylate Type III, Galβ1,4Glcβ-R, or lactose. Neither can it fucosylate acceptors that already contain an α1,3/4-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 Fucα1,2
Fuc structures, indicating the existence of an α1,2 FucT
that is capable of transferring Fuc to another Fuc residue
(Marques et al., 2001). Such an α1,2 FucT from cercariae
of the avian schistosome Trichobilharzia ocellata displayed
a relatively low catalytic efficiency for the substrate
Fucα1,3GlcNAcβ1,2Man because of its high Km (Hokke
et al., 1998). It is not yet known whether this schistosomal
enzyme contains α1,2 FucT motifs (see Sequence homology
and structural prediction of FucT subfamilies), and if it
belongs to an as yet unidentified subfamily.
a1,2 Fucosylation in bacteria
Several putative bacterial α1,2 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 α1,2
FucTs from Helicobacter pylori (Wang, Boulton, et al.,
1999; Wang, Rasko, et al., 1999). Of these enzymes, only
H. pylori α1,2 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;
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Fig. 2. Fucosylation sites of plant α1,4 FucTs, core α 1,3 FucTs, core α 1,6 FucTs, xyloglucan α 1,2 FucTs, and O-FUT1 and 2 in the structures of plant
biantennary N-glycan (A) (Vietor et al., 2003), xyloglucan (B) (Sarria et al., 2001), and proteins containing small cysteine-knot motifs with EGF repeat
(left) or thrombospondin type repeat (right) consensus sequence (C), respectively. (Wang and Spellman, 1998; Wang et al., 2001; Luo, Koles, et al., 2006;
Luo, Nita-Lazar, et al., 2006). FucTs that catalyze the fucose addition at specific linkages are shown by an arrow. Asn, asparagine; C, cysteine; Fuc,
fucose; Gal, galactose; Glc, glucose; GlcNAc, N-acetylglucosamine; Man, mannose; S, serine; T, threonine; W, tryptophan; X, any amino acid; Xyl,
xylose. The superscript on each of six conserved cysteine residue indicates their order in the small cysteine-knot motifs. The amino acids that link the conserved cysteine residues but are not part of the proposed consensus sequences are shown as a solid line.
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 α1,2 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
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sequences, an internal Shine-Dalgarno-like context, a heptamer (AAAAAAG) and the downstream potential stemloop 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 α1,2 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 α1,2 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 α1,2 FucTs lack
the N-terminal cytosolic tail and the transmembrane
domain (Wang, Boulton, et al., 1999). In fact, the α1,2
FucT from H. pylori strain UA802 was demonstrated to be
a soluble protein located in the cytoplasm (Wang, Boulton,
et al., 1999). α1,2 FucTs from different H. pylori strains
Fucosylation in prokaryotes and eukaryotes
α1,3/4 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).
a1,3/4 Fucosylation in mammals
Fig. 3. Schematic structures of (A) mammalian α1,3/4 FucTs and (B)
Helicobacter pylori α1,3/4 FucTs anchored at Golgi and H. pylori cell
membranes, respectively. The two cylinders in (B) represent two putative
amphipathic α-helices and the stem (B) corresponds to the heptad repeat
region. +, positively charged amino acid residues; CAT, catalytic domain;
COOH, C-terminus; H, hydrophobic amino acid residues; NH2,
N-terminus; P, polar amino acid residue; TM, transmembrane domain.
This figure was published previously (Ma et al., 2003).
share very high sequence identity with one another (∼95%),
but very low identity (18–22%) with their mammalian counterparts (Oriol et al., 1999).
a1,3/4 Fucosylation
α1,3/4 FucTs, belonging to CAZY family 10 (http://
afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html), add fucose at
α1,3 or α1,4 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
Mammalian α1,2 and α1,3/4 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 α1,2 linkage) followed by subterminal fucosylation (in an α1,3 or α1,4 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
α1,3/4 FucTs, abbreviated FUT3–7 and FUT9 (or FucTIII–VII and Fuc-TIX), all of which have α1,3 activity, but
FUT3 and FUT5 also possess α1,4 activity. Human α1,3/4
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 α1,4 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 α1,3
motifs (see Sequence homology and structural prediction of
FucT subfamilies) and share homology with α1,3 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 α1,4 specificity. FUT5 fucosylates H type I only on core 2
[Galβ1,3(GlcNAcβ1,6)GalNAc-Ser/Thr] structures, whereas
FUT3 fucosylates H type I much more efficiently on core 3
(GlcNAcβ1,3GalNAc-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
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Fig. 4. Biosynthesis and transport of GDP-fucose and localization of FucTs in eukaryotic cells. GDP-Fuc is synthesized in the cytosol through the de novo
synthesis and salvage pathways (Becker and Lowe, 2003; Niittymaki et al., 2004). GDP-Fuc is imported from the cytosol to the Golgi or the ER by GDPFuc transporters (Luhn et al., 2004). It is believed the ER-localized transporter is present, but it has not yet been identified. α1,2, α1,3/4 and α1,6 FucTs
are Type II membrane proteins with a N-terminal transmembrane domain anchored at the Golgi-membrane and the C-terminal catalytic region exposed to
the Golgi-lumen (Nilsson et al., 1993, 1996). α1,2 FucTs, α1,3/4 FucTs, α1,6 FucTs, and sialyltransferases, involved in terminal modifications of carbohydrate, reside in the late cisternae of the Golgi. The proper compartmentalization of α1,3/4 FucTs, α1,2FucTs, and sialyltransferases (circled in broken line)
within the Golgi is sorted by the CF transmembrane conductance regulator (Rhim et al., 2001). Mutation of this protein is responsible for impaired glycosylation in CF patients. O-FUT1 and 2 are ER-localized soluble proteins (Luo and Haltiwanger, 2005; Okajima et al., 2005). Notch has been shown to be
fucosylated first by O-FUT1 in the ER and then secreted to the cell surface aided by O-FUT1 as a chaperone (Okajima and Irvine, 2002; Okajima et al.,
2003, 2005). Whether O-fucosylation catalyzed by O-FUT1 can take place other than ER remains to be determined. Proteins with TSR sequences are
fucosylated by O-FUT2 (Luo, Koles, et al., 2006; Luo, Nita-Lazar, et al., 2006), but if it occurs in the ER awaits further examination.
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Fucosylation in prokaryotes and eukaryotes
Fig. 5. Structures of Lewis blood group antigens. Fuc, fucose; Gal, galactose; GalNAc, N-acetylgalatosamine; GlcNAc, N-acetylglucosamine.
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 phagocytophilarelated bacteria that cause human granulocytic ehrlichiosis
contain selectin-like structures on their cell surface. As a consequence, through binding to P-selectin glycoprotein ligand1 (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).
a1,4 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 α1,4 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 α1,4 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 α1,4 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 α1,4 activity. Based on the sequence
alignment, these plant α1,4 FucTs contain the Trp residue
(Bakker et al., 2001; Leonard et al., 2002) that confers the
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specificity of fucose transfer at α1,4 linkages for human
FUT3 and FUT5 (Dupuy et al., 1999, 2004). Whether the
Trp residue of plant α1,4 FucTs also confers Type I acceptor specificity awaits experimental examination.
a1,3/4 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 α1,3/4 FucTs are able to use both unsubstituted, α1,2-fucosylated and α 2,3-sialylated Type IIstructure, 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 gutassociated 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(GalNAcβ1,4GlcNAc)-repeat structure forming
Fucα1,3GalNAcβ1,4GlcNAc (Wuhrer et al., 2006). Additionally, a pseudo Ley [Fucα1,3Galβ1,4(Fucα1,3)GlcNAcβ1-R]
structure was found in cercarial extracts containing a
Fucα1,3Gal linkage (Wuhrer et al., 2000; Hokke and
Deelder, 2001). These data suggest that either schistosomal α1,3/4 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),
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and the binding ligands are Le x and pseudo-Le y
[Fucα1,3Galβ1,4(Fucα1,3)GlcNAcβ1-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. mansoniinfected 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).
a1,3/4 Fucosylation in bacteria
Putative bacterial α1,3/4 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 α1,3/4
FucTs from H. pylori have been extensively characterized.
The H. pylori genome contains two paralogous genes
futA and futB that encode two α1,3/4 FucTs, FutA and
FutB, respectively (Berg et al., 1997; Alm et al., 1999). Similar to the futC gene, futA and futB also contain the polyApolyC 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 α1,3 or α1,4 linkage)
followed by terminal fucosylation (in α1,2 linkage) (Wang
et al., 2000). Additionally, H. pylori α1,3/4 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). α1,3/4 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 α1,3/4 FucTs (i.e., from H. pylori strains
NCTC11639 and NCTC11637) have exclusive α1,3 activity
(Ge et al., 1997; Martin et al., 1997), but some (i.e., H. pylori
strains UA948 and UA1111) possess both α1,3 and α1,4
activities (Rasko, Wang, Monteiro, et al., 2000; Rasko,
Fucosylation in prokaryotes and eukaryotes
Wang, Palcic, et al., 2000). α1,3/4 FucT from strain
DMS6709 was recently reported to contain primarily α1,4
activity and only little α1,3 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 α1,3/4FucT 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 a1,3 fucosylation
Some α1,3/4 FucTs can transfer fucose from GDP-Fuc to
the innermost GlcNAc moiety of the chitobiose unit of the
core Asn-linked glycans at an α1,3 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 α1,3 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
β1,2-xylose and α1,3-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 α1,3 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 α1,3fucose and core β1,2 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 a1,3/4 FucTs
As both mammalian and H. pylori α1,3/4 FucTs have been
well characterized, they are the best FucT representatives
for inter-kingdom comparison. Alignment of the H. pylori
α1,3/4 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
165R
B. Ma et al.
α1,3/4 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 α1,3/4 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 heptadrepeat 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 α1,3/4 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 α1,3/4 FucTs, the
hydroxyl group at C-6 of galactose in Type I and Type II
acceptors is essential for recognition by H. pylori α1,3/4
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 α1,3/4 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 α1,3/4 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 α1,3/4 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
α1,3/4 FucTs very likely share a conserved mechanistic and
structural basis for fucose transfer. Such striking interkingdom 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
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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-repeatmediated 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.
a1,6 Fucosylation
FucTs that add fucose to the innermost GlcNAc moiety of
the chitobiose unit of the core Asn-linked glycans at an
α1,6 linkage are designated α1,6 FucTs (Figures 1 and 2A)
(Miyoshi et al., 1999; Yamaguchi et al., 1999, 2000). α1,6
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 α1,6 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). α1,6 FucTs are grouped into CAZY family 23 (http://
afmb.cnrs-mrs.fr/CAZY/fam/acc_GT.html).
a1,6 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. α1,6 FucT, acting at
late Golgi cisternae (Kornfeld and Kornfeld, 1985),
requires an unsubstituted β1,2-linked GlcNAc on the α1,3mannose arm of the core N-glycans (Longmore and
Schachter, 1982; Voynow et al., 1991; Uozumi et al., 1996).
Human α1,6 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 α1,2, α1,6 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
Fucosylation in prokaryotes and eukaryotes
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).
a1,6 Fucosylation in S. mansoni, insects, and C. elegans
The schistosomal egg glycoproteins contain non-fucosylated,
α1,6-monofucosylated, core α1,3/α1,6-difucosylated, and
xylosylated/α1,6-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 α1,6 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 (GalNAcβ1,4GlcNAc) with
or without fucose α1,3 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 α1,6and core α1,3-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 α1,3 FucT of Drosophila prefers core α1,6-fucosylated
glycans over the non-fucosylated forms (Fabini et al.,
2001), and honeybee-venom-gland extracts exhibit the core
α1,3 activity with monofucosylated (at 1,6 linkage) Nglycan acceptor (Staudacher et al., 1991). In contrast,
α1,6FucT seems to be no longer functional, once the
GlcNAc residue is modified by fucose addition at the α1,3
linkage. Therefore, a strict order of α1,6 fucosylation
before core α1,3 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).
a1,6 Fucosylation in Rhizobium
α1,6 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). α1,6
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 β1,4linked 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.
Xyloglucan a1,2 fucosylation
Xyloglucan α1,2 FucT is a plant α1,2 FucT, which is able
to transfer fucose to the Gal residue at the reducing end of
xyloglycan at an α1,2 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 α1,2 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 β1,4-Dglucan backbone that carries the α1,6 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 β1,2 linkage, and the second of Gal is usually
extended by fucose in an α1,2 linkage by xyloglucan α1,2
FucTs (Figure 2B). The xyloglucan containing
Fucα1,2Galβ1,2Xyl 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 α1,2 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 α1,3 FucT activity, unknown specificity, and
α1,4 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 α1,2
fucosylation of xyloglucan is not essential for plant growth.
Similarly, a T-DNA insertion in the atfut1 locus also displayed
167R
B. Ma et al.
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, Oacetylation 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, α1,2 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 α-arabinofuranosyl residue at α1,2 linkage in the primary roots of 6-day-old radish (Raphanus sativus) seedlings
(Misawa et al., 1996). Fucose was also detected in a
Fucα1,4Rhaβ 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 α1,4linkage was also found from soybean and pectin (Fransen
et al., 2000). Whether these fucose-linkages are catalyzed by
plant α1,2 and α1,4 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.
O-Fucosylation
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.cnrsmrs.fr/CAZY/fam/acc_GT.html), respectively. Human OFUT1 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/
2
3S/TC X2; 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
168R
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 β1,3-N-acetylglucosaminyltransferase,
elongates O-fucose to form a disaccharide, which is further
extended to a tetrasaccharide (Rampal et al., 2005). The Ofucose on TSRs, in constrast, is elongated with a glucose moiety to form a disaccharide by β1,3-glucosyltransferase
(Sato et al., 2006; Luo, Nita-Lazar, et al., 2006). Fringe
enzymes and β1,3-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 wildtype 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).
Sequence homology and structural prediction of FucT
subfamilies
To detect motifs common to α1,2, α1,3/4, and α1,6 FucTs,
hydrophobic cluster analysis (HCA) was carried out to align
Fucosylation in prokaryotes and eukaryotes
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 α1,2 and α1,6 FucT families; two unique for
α1,3/4 FucTs; one specific for α1,2 FucTs; and another specific for α1,6 FucTs (Oriol et al., 1999). Recently, a third
motif common to α1,2 and α1,6 FucTs from both prokaryotic and eukaryotic origins was identified (Chazalet et al.,
2001). Although α1,3 FucTs lack the consensus peptide segments shared by α1,2 and α1,6 FucTs, the first α1,3 FucT
motif and the first α1,2/α1,6 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 α1,6 FucT (NodZ)
and O-FUT1/2 contained three motifs common to α1,2 and
α1,6 FucTs (Chazalet et al., 2001; Martinez-Duncker et al.,
2003). Moreover, NodZ seems to share more similarities to
plant α1,2 FucTs: two regions (a and b) at the N-terminal
side of catalytic domain are conserved between NodZ and
plant α1,2 FucTs (Chazalet et al., 2001). Phylogenic analysis has suggested that O-FUTs are more related to α1,6
FucTs than to α1,2 FucTs (Martinez-Duncker et al., 2003).
Interestingly, plant xyloglucan α1,2 FucTs possess not only
motif I that is common to α1,2 and α1,6 FucTs but also
two short segments corresponding to motif III unique to
α1,2 FucT and α1,6 FucT families, respectively (Faik et al.,
2000). All these data suggest that α1,2, α1,6, O-FUTs, xyloglucan α1,2, and α1,3/4 FucTs are likely descended from a
common ancestor, but α1,3/4 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 α1,2 and
α1,3 FucTs share the GT-B fold with β-glucosyltransferase
from bacteriophage T4 (BGT). The GT-B fold consists of
two domains with an α/β/α 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
α1,6 FucT (NodZ) contained a Rossman fold at the Cterminal part of the catalytic domain. They also predicted
that α1,2, α1,3/4, and α1,6 FucTs all adopt a standard
three layer α/β/α sandwich structure, with the BGT fold
giving the highest score. Other studies based on PSIBLAST search and structural analysis (Wrabl and Grishin,
2001; Liu and Mushegian, 2003) confirmed that α1,3/4
FucTs adopt a GT-B fold; however, α1,2 and α1,6 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 βstrand-loop-α-helix-turn units, and thus, remodeling analysis may have difficulty in distinguishing it from a α/β/α
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.
Abnormal fucosylation in mammals
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 α1,2,
α1,3/4, and α1,6 linkages in their fibroblasts but little
decrease in O-fucosylation (Sturla et al., 2003). Notably,
core α1,6 fucosylation was diminished to the greatest
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B. Ma et al.
extent, even though both expression and activities of α1,6
FucT were not significantly modified (Sturla et al., 2003,
2005). The reduction of core α1,6 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 Gftdefective 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 α1,6
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 GDPFuc compared with α1,2, α1,3/4, and α1,6 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-/Lselectin 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 a1,2 fucosylation and diseases
To study the effects of α1,2 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 α1,2 fucosylation is not indispensable for development. Nonetheless,
the secretor status that is controlled by fut2 and controls
the appearance of α1,2-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 nonsecretor 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
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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 nonprogressive 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 a1,3 fucosylation and diseases
During inflammation and cancer, α1,3 fucosylation is often
found to be increased (Mackiewicz and Mackiewicz, 1995),
and such an increase is mainly observed in α1-acid glycoprotein (AGP) (Higai et al., 2003, 2005). AGP is a serum
acute phase glycoprotein containing five potential Asnlinked glycosylation sites. The N-glycosylation of AGP
may form bi-, tri-, and tetra-antennary structures, some of
which are α1,3 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 α1,3 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 α1,3
fucosylation of AGP was observed in patients with Type I
diabetes mellitus and a direct correlation between α1,3 fucosylation level in AGP and urinary albumin secretion was
found, suggesting that α1,3 fucosylation of AGP might be
another marker for monitoring disease progress (Poland et al.,
2001). In addition, enhanced α1,3 fucosylation of AGP was
also reported in rheumatoid arthritis patients (Elliott et al.,
1997; Ryden et al., 2002). Studies have shown that α1,3 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, α1,3 fucosylation and
α1,6 fucosylation were greatly increased, whereas α1,2 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 α1,3 FucTs
(FUT3, 4, and 7), sialyltransferases, and α1,2 FucTs in the
extracts of airway epithelial cells of CF patients, however,
Fucosylation in prokaryotes and eukaryotes
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 ΔF508 (Riordan et al.,
1989). Under normal conditions, the α1,3 FucTs act subsequent to sialyltransferases and α1,2 FucTs. However, when
CFTR is mutated, the compartmentalization of the terminal glycosyltransferases in the Golgi is disrupted so that the
α1,3 FucTs are sorted into a position before the sialyltransferases and α1,2FucTs (Allan and Balch, 1999). As a consequence, the sialyltransferases and α1,2 FucTs may fail to
recognize the substrates that were already α1,3/4-fucosylated,
and both sialylation and α1,2 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 α1,3-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 α1,3fucosylation 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 PAIIL, whereas Lex, sialyl-Lex, and D-mannose conferred
much weaker binding to PA-IIL (Mitchell, Houles, et al.,
2002).
Abnormal a1,6 fucosylation and diseases
FUT8 is the only enzyme responsible for adding fucose to
the Asn-linked GlcNAc moiety at α1,6-linkages on the core
structure of N-glycans. To examine the consequences of
void α1,6-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 overexpression 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 β1 (TGF-β1)
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-β1 receptor binding, and the
complementation of exogenous TGF-β1 rescued both
emphysema-like lung changes and the overexpression of
matrix metalloproteinases. Therefore, core α1,6 fucosylation of TGF-β1 receptor is crucial for proper function of
TGF-β1 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, α1,6 core
fucosylation seems essential for both TGF-β1 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, α-fetoprotein, a wellknown 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
α1,6FucT 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–/–
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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.
Application of FucTs, fucosylated oligosaccharides
and FucT inhibitors
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
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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 selectinmediated 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
Fucosylation in prokaryotes and eukaryotes
(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 surfaceexposed 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 ABOincompatible transplantation.
Fucosylated oligosaccharides in cancer vaccines. The fucosecontaining 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
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B. Ma et al.
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 α2,3 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 Eselectin 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,
174R
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 α1,3
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.
Concluding remarks
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, α1,3/4 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 (α1,2 FucTs, α1,6FucTs, O-FUT1/2,
and xyloglucan α1,2 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.
Fucosylation in prokaryotes and eukaryotes
Supplementary Data
Supplementary data are available at Glycobiology online
(http://glycob.oxfordjournals.org/).
Acknowledgments
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.
Conflict of interest statement
None declared.
Abbreviations
AGP, α1-acid glycoprotein; BabA, Leb binding adhesin;
BGT, β-glucosyltransferase from bacteriophage T4;
CAZY, Carbohydrate-Active enZYmes; CF, cystic fibrosis;
CFTR, cystic fibrosis transmembrane conductance regulator; DC-SIGN, dendritic cell-specific ICAM-grabbing nonintegrin; 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-β1, transformation growth factor-β1; TSR,
thrombospondin type repeat; Type I, Galβ1,3GlcNAc; Type
II (LacNAc), Galβ1,4GlcNAc; Type III, Galβ1,3GalNAc.
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