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Fucose: biosynthesis and biological function in mammals

 
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Abstract

Fucose is a deoxyhexose that is present in a wide variety of organisms. In mammals, fucose-containing glycans have important roles in blood transfusion reactions, selectin-mediated leukocyte-endothelial adhesion, host–microbe interactions, and numerous ontogenic events, including signaling events by the Notch receptor family. Alterations in the expression of fucosylated oligosaccharides have also been observed in several pathological processes, including cancer and atherosclerosis. Fucose deficiency is accompanied by a complex set of phenotypes both in humans with leukocyte adhesion deficiency type II (LAD II; also known as congenital disorder of glycosylation type IIc) and in a recently generated strain of mice with a conditional defect in fucosylated glycan expression. Fucosylated glycans are constructed by fucosyltransferases, which require the substrate GDP-fucose. Two pathways for the synthesis of GDP-fucose operate in mammalian cells, the GDP-mannose-dependent de novo pathway and the free fucose-dependent salvage pathway. In this review, we focus on the biological functions of mammalian fucosylated glycans and the biosynthetic processes leading to formation of the fucosylated glycan precursor GDP-fucose.

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Introduction

L-fucose (6-deoxy-L-galactose) is a monosaccharide that is a common component of many N- and O-linked glycans and glycolipids produced by mammalian cells. Two structural features distinguish fucose from other six-carbon sugars present in mammals. These include the lack of a hydroxyl group on the carbon at the 6-position (C-6) and the L-configuration. Fucose frequently exists as a terminal modification of glycan structures; however, recently glycosyltransferase activities capable of adding sugars directly to fucose have been identified (Moloney and Haltiwanger, 1999). Specific terminal glycan modifications, including fucosylation, can confer unique functional properties to oligosaccharides and are often regulated during ontogeny and cellular differentiation. Important roles for fucosylated glycans have been demonstrated in a variety of biological settings (Listinsky et al., 1998; Staudacher et al., 1999), several of which are reviewed shortly. However, because of the diversity of fucose-containing glycoconjugates and the difficulties inherent in studying the biological function of carbohydrates, it is likely that many additional functions for fucosylated glycans remain to be uncovered.

Fucosylated glycans are synthesized by fucosyltransferases (Table I). Thirteen fucosyltransferase genes have thus far been identified in the human genome. FUT1 and FUT2 are α(1,2)-fucosyltransferases responsible for synthesis of the H blood group antigen and related structures (Kelly et al., 1995; Larsen et al., 1990). FUT3-FUT7 and FUT9 encode fucosyltransferases that synthesize α(1,3)- and, in the case of FUT3, α(1,4)-fucosylated glycans, such as the Lewisx and sialyl Lewisx antigens (Kaneko et al., 1999; Natsuka and Lowe, 1994). FUT8 is an α(1,6)-fucosyltransferase that directs addition of fucose to asparagine-linked GlcNAc moieties, a common feature of N-linked glycan core structures (Miyoshi et al., 1999). POFUT1 encodes an O-fucosyltransferase that adds fucose directly to polypeptide chains (Wang et al., 2001). Finally, though not yet validated by functional studies, two additional putative α(1,3)-fucosyltransferase genes, FUT10 and FUT11, and one additional putative O-fucosyltransferase gene, O-FUT2, have been identified in the human genome by comparison with fucosyltransferase sequences in the Drosophila melanogaster genome (Roos et al., 2002).

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Table I.

Human fucosyltransferases

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Fucosylated glycans: physiological and pathophysiological significance

Fucosylated glycans and the ABO blood group

The ABO blood group antigens are among the most well-known fucosylated glycans. The H transferase (FUT1 gene product) is an α(1,2)-fucosyltransferase expressed in erythroid precursors that synthesizes a structure known as the H antigen by directing the addition of fucose to terminal galactose residues on oligosaccharide precursors decorating several glycoproteins and glycolipids (Figure 1A). In epithelial tissues and salivary glands, a second α(1,2)-fucosyltransferase known as the Secretor (Se) transferase (FUT2 gene product) synthesizes the H antigen. In individuals of blood group A, B, or AB, the H antigen may be further modified by the ABO locus-encoded glycosyltransferase to form the A and B antigens; unmodified H antigen is expressed on the cell surface of type O individuals (Figure 1A) (Lowe, 1993). The A, B, and H antigens are highly immunogenic, and high titers of complement-fixing IgM against these molecules prevent successful red blood cell transfusions to incompatible individuals. The functional significance for ABO antigen expression on erthyrocytes has not been defined, but ABO-related structures may play a role in other systems.

Fig. 1.
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Fig. 1.

Structures of common fucosylated glycans. (A) Synthesis of ABO blood group antigens. The H and Se transferases are a pair of α(1,2)-fucosyltransferases that synthesize the H antigen in a variety of tissues. The ABO locus encodes a glycosyltransferase that further modifies the H antigen. The A allele at the ABO locus encodes an N-acteylgalactosaminyltransferase. The B allele encodes a galactosyltransferase that differs from the A transferase at four amino acid positions. The O allele at the ABO locus encodes a truncated, enzymatically inactive protein. (B) Lewis-related antigens. Circles indicate the immunodominant portion of each antigen. (C) A representative O-linked fucose glycan. Fucose modifies serines or threonine within the broad consensus site shown here, and in Table I. R indicates glycolipid and N- and O-linked glycoprotein precursors.

Plasma levels of von Willebrand factor (VWF), an essential coagulation protein, vary widely between individuals, and genotype at the ABO and Se loci have been shown to be determinants of this variability. Because variation in VWF level contributes to disease severity in von Willebrand disease patients (Levy and Ginsburg, 2001), as well as predisposition toward clotting-related conditions, such as recurrent venous thromboembolism and ischemic heart disease in the general population (O'Donnell and Laffan, 2001), the medical importance of the ABO system may thus extend beyond blood typing issues. The molecular basis for modulation of VWF by fucosylated glycans has not been directly addressed experimentally, but a mechanism based on differential clearance of glycan-modified VWF by hepatic carbohydrate-recognition receptors has been proposed (Levy and Ginsburg, 2001).

Fucosylated glycans in host–microbe interactions

Fucosylated blood group antigens may also be important for host–microbe interactions. The gastric pathogen Helicobacter pylori is capable of attachment to the gastric epithelium via host expression of the Lewisb antigen, a structure containing α(1,2)- and α(1,4)-linked fucose that is synthesized by the concerted action of the Se and Lewis (FUT3) fucosyltransferases (Figure 1B). This Lewisb-determined interaction may contribute to development of H. pylori–mediated peptic ulcer disease because masking of Lewisb with terminal GalNAc by the A transferase abolishes bacterial binding and correlates with the decreased ulcer incidence observed in A and B blood group individuals (Hooper and Gordon, 2001). Moreover, overexpression of the Lewis transferase in the gastric pit cells of mice, an organism that normally does not produce Lewisb, leads to Lewisb expression and increased severity of gastritis following H. pylori inoculation (Guruge et al., 1998). In addition to Lewis antigen expression by the host, H. pylori cells also produce Lewis-related structures, such as Lewisx, Lewisy, and Lewisb (Figure 1B), an example of molecular mimicry (Appelmelk et al., 1997). Expression of these fucosylated glycans by H. pylori increases at acid pH (Moran et al., 2002), coincident with up-regulation of a fucose biosynthetic gene (McGowan et al., 1998), and may induce autoimmune-mediated damage to the gastric epithelium, leading to chronic atrophic gastritis in a subset of H. pylori–infected humans (Hooper and Gordon, 2001).

In addition to expression by some gastric cell lineages, glycans containing α(1,2)-linked fucose are also abundantly expressed by intestinal epithelium of adult mammals (Torres-Pinedo and Mahmood, 1984). During the weaning transition in rats, as the developing animal switches to solid food, the intestine undergoes a profound transformation that includes increased fucose biosynthetic capacity (Ruggiero-Lopez et al., 1991), up-regulation of fucosyltransferase activity (Biol et al., 1987), and increased fucosylated glycan expression. The shift toward fucosylation in the adult intestine can be accelerated by administration of insulin or prevented by prolonged suckling (Biol et al., 1998), indicating that specific signals control this developmental program. Experiments with germ-free mice have demonstrated that maintenance of α(1,2)-fucosyltransferase mRNA and α(1,2)-fucosylated glycan expression after weaning depends on the presence of normal microflora, and colonization by a single component of the flora, Bacteroides thetaiotamicron, which restores fucosyltransferase and fucosylated glycan expression (Bry et al., 1996). Moreover, an exquisite system for controlling the expression of fucose catabolism genes by sensing fucose availability has been described in B. thetaiotamicron. Indirect genetic evidence suggests that the fucose-sensing protein in B. thetaiotamicron is also capable of inducing the host intestine to increase expression of fucosylated glycans and thereby increase bacterial fucose supply (Hooper et al., 1999). These observations imply that α(1,2)-fucosylated glycan expression contributes to establishment of the indigenous microbial community in the developing gut by providing a favorable ecological niche for specific nonharmful commensal organisms capable of utilizing fucose as a carbon source (Hooper et al., 2000).

Contributions of fucosylated glycans to selectin-dependent leukocyte adhesion

One of the best-studied functions of fucose is its role as an essential component of the carbohydrate ligands for the selectin family of cell adhesion receptors (Kansas, 1996; Vestweber and Blanks, 1999). E-, P-, and L-selectin are C-type lectin proteins expressed by platelets (P-selectin), endothelial cells (E- and P-selectin), and leukocytes (L-selectin). Selectins bind to oligosaccharides, decorating specific cell surface and secreted proteins expressed by leukocytes (E- and P-selectin ligands) and high endothelial venules (L-selectin ligands). Interaction between selectins and their ligands enable the rolling of leukocytes on the endothelium, the required first step in leukocyte extravasation (Springer, 1994). The carbohydrate selectin ligands are fucosylated structures related to the sialyl Lewisx structure (Figure 1B). Two α(1,3) fucosyltransferases, Fuc-TVII (FUT7 gene product) and Fuc-TIV (FUT4 gene product), are expressed in leukocytes and endothelial cells and catalyze the final reaction in selectin ligand biosynthesis, the addition of fucose to sialylated precursors (Lowe, 1997; Natsuka and Lowe, 1994; Smith et al., 1996). Gene ablation experiments in mice have established that Fuc-TVII is essential for proper recruitment of neutrophils and T cells to inflammatory sites and lymphocyte trafficking to secondary lymphoid organs (Maly et al., 1996; Smithson et al., 2001). In contrast, although neutrophils in Fuc-TIV–/– mice have been observed to roll on the dermal microvasculature at a higher velocity than wild-type neutrophils (Weninger et al., 2000), the contribution of Fuc-TIV to neutrophil and lymphocyte recruitment is much smaller than the contribution of Fuc-TVII and has thus far been apparent only in the context of deficiency for both Fuc-TIV and Fuc-TVII (Homeister et al., 2001; Smithson et al., 2001).

Fucosylated glycans in development

There is evidence for involvement of fucosylated glycans in ontogenic events. The Lewisx epitope, an α(1,3)-fucosylated glycan also known as the stage-specific embryonic antigen-1 and CD15, is expressed during early embryogenesis (Solter and Knowles, 1978). Exposure of preimplantation mouse embryos at the morula stage to oligosaccharides containing multivalent Lewisx structures causes decompaction, implying that Lewisx promotes cell–cell adhesion in early embryos (Bird and Kimber, 1984; Fenderson et al., 1984). Carbohydrate–carbohydrate interactions, that is, Lewisx interacting with itself, are thought to form the molecular basis for Lewisx-mediated embryo compaction (Eggens et al., 1989). Lewisx epitopes are also present in multiple areas of the embryonic brain (Ashwell and Mai, 1997a,b,c,d), controlled by expression of Fuc-TIX (FUT9 gene product), which is in turn controlled by expression of Pax6, a transcription factor important for neural development (Shimoda et al., 2002). The biological significance of Lewisx in the developing brain is not known, but its dynamic expression pattern at different embryonic stages has led many to infer important functions during neurogenesis (Kudo et al., 1998).

O-linked fucosylation of EGF-like domains and signal transduction

In contrast to its role as a terminal modification of oligosaccharides, fucose may also be found in direct linkage to hydroxyl groups of serine and threonine residues. This glycosylation event, known as O-fucosylation, is carried out by one or more Golgi-resident O-fucosyltransferases (Wang et al., 2001; Wang and Spellman, 1998) that act on specific consensus sequences in epidermal growth factor (EGF)-like modules of cell surface and secreted proteins, including several blood coagulation factors (Harris and Spellman, 1993; Moloney and Haltiwanger, 1999). O-fucose residues do not appear to affect tertiary protein structure because O-fucosylation of an EGF domain from Factor VII does not alter solution structure or binding affinity for tissue factor (Kao et al., 1999). However, O-fucosylation can have important functional consequences. Defucosylation of the EGF domain from urokinase-type plasminogen activator abolishes its mitogenic activity despite having no effect on binding to the cell surface (Rabbani et al., 1992), suggesting that O-fucose can qualitatively affect ligand–receptor interactions necessary for productive signal transduction events. Supporting this notion, mutation of an O-fucosylation site in the EGF domain of human Cripto-1, a glycosylphosphatidylinositol-anchored protein critical for early embryogenesis (Ding et al., 1998; Minchiotti et al., 2000), reduces its ability to facilitate signaling by the tumor growth factor β family member Nodal (Schiffer et al., 2001).

O-fucose residues are also present on EGF domains of the mammalian Notch receptors (Moloney et al., 2000b), a family of transmembrane signaling proteins with important roles in cell fate determination during somite formation, neurogenesis, angiogenesis, and lymphoid development (Artavanis-Tsakonas et al., 1999). Ligand-induced Notch signaling events are impaired in a fucose-deficient cell line but can be restored by correction of the fucosylation defect, implying that O-fucosylation of Notch affects its interaction with and/or its response to ligands (Chen et al., 2001; Moloney et al., 2000a). In Drosophila, O-linked fucose is apparently essential to Notch signaling events and corresponding cell fate determination (Okajima and Irvine, 2002). Notch signaling is modulated in a number of contexts by expression of Fringe genes (Panin and Irvine, 1998), which have recently been shown to encode glycosyltransferases that direct addition of GlcNAc to O-fucose residues on Notch (Bruckner et al., 2000; Moloney et al., 2000a). Fringe-mediated extension of O-fucose differentially impacts Notch activity in response to ligands, demonstrating that an additional function for O-fucose on Notch is to serve as the required substrate for Fringe (Bruckner et al., 2000; Hicks et al., 2000; Moloney et al., 2000a; Shimizu et al., 2001). Further, O-fucosylation of Notch and/or other yet-to-be-discovered Fringe substrates may be essential to normal mammalian development because targeted mutation of one of the Fringe genes in mice causes severe defects in somite formation and early demise (Evrard et al., 1998; Zhang and Gridley, 1998).

Recent evidence indicates that O-fucosylation is not limited to EGF domains, as glucose-extended fucose modifications (Glc-Fuc-O-Ser/Thr) have been demonstrated in three thrombospondin type 1 repeats of thrombospondin-1 (Hofsteenge et al., 2001). Functional investigation of O-fucosylation on thrombospondin type 1 repeats, however, has not yet been reported. It remains to be determined if additional protein modules are also modified by O-fucosylation.

Fucosylated glycans in human disease

Fucosylated glycans have been implicated in the pathogenesis of several human diseases. Two prominent examples of altered glycosylation in cancer involve fucose-containing oligosaccharides. First, expression of A and B blood group antigens is lost in many tumors with concomitant increases in H and Lewisy expression, changes that correlate with poor clinical prognosis (Kim and Varki, 1997; Lee et al., 1991; Miyake et al., 1992; Orntoft and Vestergaard, 1999). Second, up-regulation of sialyl Lewisx and sialyl Lewisa (Figure 1B) has been demonstrated in numerous cancers, and these increases are also associated with advanced tumor grade and poor prognosis. Sialyl Lewisx and sialyl Lewisa serve as ligands for the selectin molecules and thus may aid in hematogenous metastasis by direct binding of cancer cells to E- and P-selectin expressed by the endothelium (Kannagi, 1997; Kim and Varki, 1997). Other possible mechanisms for sialyl Lewisx/a-mediated metastasis include formation of cellular thromboemboli via interaction with platelet-borne P-selectin (Borsig et al., 2001) and blockade of leukocytic infiltration into tumors by secretion of sialyl Lewisx/a-containing inhibitors of leukocyte-endothelial adhesion (Kim and Varki, 1997). Moreover, increased α(1,6)-fucosylation of α-fetoprotein is observed in hepatocellular carcinoma patients and can be used clinically as a marker for distinguishing hepatocellular carcinoma from chronic liver disease (Miyoshi et al., 1999).

Increased expression of fucosylated glycans has also been reported on serum immunoglobins in both juvenile and adult rheumatoid arthritis patients (Flogel et al., 1998; Gornik et al., 1999). It is not known if such changes are important to the pathogenesis of inflammatory arthritis or if they represent a secondary consequence due to up-regulation of the fucosylation machinery in the context of autoimmunity. Similarly, fucosylation of mucins has been observed to be increased in cystic fibrosis, with a concomitant decrease in sialylation (Scanlan and Glick, 1999). In a murine model of this disease, increased fucosylation of small bowel mucin correlates with substantially increased expression of the murine Fut2 α(1,2)-fucosyltransferase mRNA (Thomsson et al., 2002). It remains to be determined if there are causal relationships between these observations and aberrant microbial colonization that characterize the pathogenesis of cystic fibrosis. Last, as a result of their role in leukocyte recruitment, selectin–selectin ligand interactions contribute to the development of numerous pathological processes, including atherosclerosis, reperfusion injury following ischemic events, inflammatory skin diseases, and asthma (Varki, 1999).

Mammalian cell lines that lack cell surface fucosylated glycan expression are viable with no apparent defect in cell division (Reitman et al., 1980; Ripka et al., 1986). This is perhaps not surprising because many of the functions of fucosylated glycans depend on cell–cell interactions, developmental processes, or host–microbe interactions. However, mammals exhibiting a global deficiency in fucosylated glycans have severe defects in multiple systems. Sharp reductions in cell surface fucosylated glycans are observed in humans with leukocyte adhesion deficiency type II (LAD II; also known as congenital disorder of glycosylation IIc) (Becker and Lowe, 1999). These patients suffer recurrent infections consequent to defective selectin ligand biosynthesis. In addition, mental retardation and skeletal abnormalities are also prominent features in LAD II, but it is not known if these conditions result from defects in fucose-dependent processes, such as O-fucosylation of Notch receptors or Lewisx interactions in the embryonic brain. The molecular basis of LAD II is discussed in more detail (see Salvage pathway). Mice engineered to have a conditional impairment in fucosylated glycan expression also exhibit a pleiotropic phenotype that includes altered myeloid development, diarrhea with inflammatory bowel disease-like histology, and infertility (Smith et al., 2002). Because fucosylated glycan expression can be reversibly and rapidly controlled in these mice, this knockout mouse strain should be an important tool for elucidating the many previously unrecognized and unexplored functions for fucose-containing glycoconjugates. The observation that fucose deficiency in animals causes a large number of phenotypic consequences underscores the crucial role of fucosylated glycans to many physiological and developmental processes.

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Fucose metabolism

All fucosyltransferases utilize a nucleotide-activated form of fucose, GDP-fucose, as a fucose donor in the construction of fucosylated oligosaccharides. Two pathways have been described for synthesis of GDP-fucose in the cytosol of essentially all mammalian cells. These are termed the de novo pathway and the salvage pathway (Figure 2) (Tonetti et al., 1998). The de novo pathway transforms GDP-mannose to GDP-fucose via three enzymatic reactions carried out by two proteins, GDP-mannose 4,6-dehydratase (GMD) and a second enzyme, GDP-keto-6-deoxymannose 3,5-epimerase, 4-reductase, also known as the FX protein (Tonetti et al., 1996). The salvage pathway synthesizes GDP-fucose from free fucose derived from extracellular or lysosomal sources. Quantitative studies of fucose metabolism in HeLa cells indicate that greater than 90% of GDP-fucose is derived from the de novo pathway, even in cells fed radiolabeled fucose (Yurchenco and Atkinson, 1975, 1977). Nevertheless, as will be discussed, the existence of the salvage GDP-fucose biosynthetic pathway has proven useful for correction of fucosylation defects in LAD II patients, FX–/– mice, and mutant cell lines and thus has considerable importance for the study of fucosylation processes in mammals. Both pathways are discussed in detail in the following sections.

Fig. 2.
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Fig. 2.

Biosynthesis of GDP-fucose. In mammalian cells, GDP-fucose is synthesized by two distinct pathways. The de novo pathway is characterized by conversion of GDP-mannose to GDP-4-keto-6-deoxymannose by GMD. This keto intermediate is then converted to GDP-fucose by an epimerase/reductase known as the FX protein. An alternative salvage pathway can yield GDP-fucose derived directly from fucose. The salvage pathway utilizes fucose that is transported into the cytosol from an extracellular origin or fucose that is liberated from catabolism of fucosylated glycans in the lysosome and then transported into the cytosol. The salvage pathway is enabled by fucose kinase and GDP-fucose pyrophosphorylase, with fucose-1-phosphate is the metabolic intermediate. GDP-fucose synthesized by these pathways is then transported into the lumen of the Golgi apparatus where it becomes available to the catalytic domains of fucosyltransferases that also localize to this membrane-delimited compartment within the secretory pathway.

De novo pathway

The de novo pathway for GDP-fucose biosynthesis was first proposed over 40 years ago by Victor Ginsburg, whose pioneering work demonstrated that GDP-mannose was converted to GDP-fucose via a keto-containing intermediate, GDP-4-keto-6-deoxymannose (Ginsburg, 1960, 1961a,b). The first reaction in the de novo pathway is carried out by GMD, which converts GDP-mannose to GDP-4-keto-6-deoxymannose by catalyzing the oxidation of the hydroxyl group at C-4 of the mannose ring coupled with reduction of the hydroxyl at C-6 (Figure 2). GMD requires a stably bound nicotinamide adenine dinucleotide phosphate+ (NADP) cofactor, which serves as a shuttle for transfer of electrons from C-4 to C-6 (Chang et al., 1985; Oths et al., 1990; Somoza et al., 2000; Sullivan et al., 1998; Yamamoto et al., 1993).

GMD is conserved throughout evolution; nucleotide sequences for GMD from over 20 bacterial species, plants (Arabidopsis), invertebrates (C. elegans, D. melanogaster), and mammals (human, mouse expressed sequence tag) have been deposited in GenBank (Becker, unpublished data; Lamrabet et al., 1999; Ohyama et al., 1998; Roos et al., 2002; Somoza et al., 2000; Stevenson et al., 1996; Sullivan et al., 1998). GMD transcripts are ubiquitously expressed in most or all human tissues, although the transcript levels vary considerably between tissues (Sullivan et al., 1998). The crystal structure of Escherichia coli GMD has been solved (Somoza et al., 2000), demonstrating that GMD is a member of the short chain dehydrogenase/reductase (SDR) family (Jornvall et al., 1995). GMD is a homodimeric protein with each monomer consisting of two domains, an NADP+ binding N-terminal domain and a nucleotide sugar binding C-terminal domain (Somoza et al., 2000). GDP-fucose is a potent competitive inhibitor of GMD (Albermann et al., 2000; Bisso et al., 1999; Broschat et al., 1985; Kornfeld and Ginsburg, 1966; Somoza et al., 2000; Sturla et al., 1997; Sullivan et al., 1998), thus demonstrating a classic example of feedback inhibition by the final product of the pathway.

GDP-4-keto-6-deoxymannose produced by GMD is then converted to GDP-fucose by a dual functional epimerase-reductase enzyme known as the FX protein (Chang et al., 1988; Tonetti et al., 1996). In the first reaction carried out by the FX protein, the hydroxyl group at C-3 and the methyl group at C-5 of the mannose ring are epimerized to yield GDP-4-keto-6-deoxygalactose. The 4-reductase activity of FX protein then catalyzes a hydride transfer from the required Nicotinamide adenine dinucleotide phosphate, reduced form, (NADPH) cofactor to the keto group at C-4, yielding GDP-fucose and NADP+ (Figure 2) (Menon et al., 1999).

The FX protein was first isolated and characterized in the mid-1970s by Antonio De Flora and colleagues who, while purifying glucose-6-phosphate dehydrogenase from human erthyrocytes, observed the presence of an additional, contaminating NADP(H)-binding protein. As their initial studies failed to determine the identity of the copurified protein, they coined the moniker FX to indicate its unknown function (De Flora et al., 1975, 1977b; Morelli et al., 1977; Morelli and De Flora, 1977). Twenty years after its initial identification, De Flora and colleagues determined by amino acid sequencing that the FX protein is the human homolog of a previously characterized mouse protein known as tissue-specific transplantation antigen P35B (Camardella et al., 1995). A dominantly acting point mutation in the gene encoding P35B causes major histocompatibility complex (MHC)-mediated immune rejection and loss of tumorgenicity in a mouse mastocytoma clone (Szikora et al., 1990). Although it is not known if the P35B mutation affects FX enzymatic function in the mastocytoma clone, the observation that the P35B amino acid substitution generates an MHC-binding neoantigenic peptide (Szikora et al., 1993) implies that the role of the FX protein as a transplantation antigen is unrelated to its function in GDP-fucose biosynthesis. However, examination of the P35B (i.e., FX) cDNA sequence disclosed homology to bacterial genes encoding enzymes proposed to mediate nucleotide sugar metabolism, leading to the discovery that the FX protein represents the mammalian GDP-fucose synthetase (Tonetti et al., 1996). Comparison between FX cDNA sequences disclosed a remarkable evolutionary conservation with 93% sequence identity (98% similarity) between human and mouse, and 50% identity of a 670 nucleotide region between human and E. coli (Tonetti et al., 1996). The crystal structure of the E. coli homolog of the FX protein has been determined, revealing that the FX protein is also a member of the SDR family with a structure similar to GMD, including homodimerization and a two-domain structure of the monomer subunits analogous to the domains of GMD (Rizzi et al., 1998; Rosano et al., 2000; Somers et al., 1998).

Biosynthesis of GDP-fucose from GDP-mannose can be reconstituted in vitro, both with cytosolic extracts and recombinant enzymes. Multiple laboratories working with many different tissues and species have observed that the activity of GMD in cellular extracts can be measured independently from FX activity by omitting the FX proteins required NADPH cofactor from the reaction mixture (Bonin et al., 1997; Ginsburg, 1961b; Liao and Barber, 1971; Reitman et al., 1980; Ripka et al., 1986). In the absence of exogenous NADPH, both the epimerase and reductase functions of the FX protein are apparently inactive, leading to accumulation of the product of GMD, GDP-4-keto-6-deoxymannose.

Cytosolic assays performed in the presence of NADPH measure the concerted action of GMD and FX. The one published exception to this paradigm was observed in a study of Nereid seaworm lysates. In that study, significant production of GDP-4-keto-6-deoxygalactose, the product of the epimerase activity of the FX protein, was observed in the absence of NADPH (Bulet et al., 1984). Molecular cloning of the cDNAs encoding GMD and FX allowed for reconstitution of the de novo pathway with recombinant, bacterially expressed GMD and FX proteins (Sullivan et al., 1998). Reactions with recombinant GMD and millimolar quantities of GDP-mannose proceed to completion. Subsequent addition of FX protein and NADPH yields stoichiometric quantities of GDP-fucose (Albermann et al., 2000; Sullivan et al., 1998). “One-pot” synthesis of GDP-fucose from GDP-mannose is not possible, however, because of feedback inhibition of GMD by GDP-fucose (Albermann et al., 2000). Experiments with the E. coli homolog of FX protein reveal that the epimerase activity can be active in the absence of NADPH, at least for recombinant protein in the presence of high substrate concentrations (Menon et al., 1999).

There is evidence that the de novo GDP-fucose biosynthetic pathway is subject to regulatory control in a variety of biological contexts. For example, GMD and FX activities increase during the nutrional transition associated with weaning in the rat intestine (Ruggiero-Lopez et al., 1991), in parallel with increased intestinal fucosyltransferase activities, and fucosylated glycan expression (Chu and Walker, 1986; Torres-Pinedo and Mahmood, 1984). These observations imply the existence of mechanisms that coordinately control the elaboration of fucosylated glycans. Dynamic control of GMD activity has also been observed in a species of Nereid seaworms, where oocyte maturation is accompanied by increased GMD activity (Bulet et al., 1984) and a concomitant increase in the content of protein-bound fucose. Regulated increases in the expression of FX mRNA and/or FX protein have been observed in glucose-6-phosphate dehydrogenase deficiency in human erthyrocytes (De Flora et al., 1977a), in association with acid pH stress in H. pylori (McGowan et al., 1998), following antibody-mediated stimulation of human squamous cell carcinoma cell lines (Eshel et al., 2000), and after polyclonal activation of human lymphocytes (Eshel et al., 2001).

Salvage pathway

The existence of an alternative salvage pathway for GDP-fucose biosynthesis was first inferred from studies in which radiolabeled fucose was administered to rats or provided in the culture medium of HeLa cells (Coffey et al., 1964; Kaufman and Ginsburg, 1968). These experiments demonstrated that fucose is directly incorporated into glycoproteins with little or no conversion to other sugars, thus indicating that fucose can be directly “activated” to GDP-fucose by means of a pathway independent of GDP-mannose. Free fucose derived from dietary sources or, in the case of cultured cells, from the culture medium, is transported across the plasma membrane into the cytosol. Relatively little is known about the cell surface fucose transport system, but it appears to operate by facilitated diffusion and to be specific for fucose (Wiese et al., 1994). In this context, there is evidence that in rats, fucose is a competitive inhibitor of a plasma membrane sodium-dependent myo-inositol transport system and that very high levels of dietery fucose can deplete cellular myo-inositol pools (Yorek et al., 1993). However, the molecular relationship between plasma membrane transporter(s) for myo-inositol and fucose transporters is not yet defined. Free fucose that supplies the salvage pathway may also derive from lysosomal catabolism of glycoproteins and glycolipids by one or more fucosidase activities (Johnson and Alhadeff, 1991; Michalski and Klein, 1999). Fucose liberated in the lysosomal compartment can be transported across the lysosomal membrane into the cytosol by a relatively uncharacterized transport system that appears to allow efflux of multiple neutral sugars by facilitated diffusion (Jonas et al., 1990).

Free fucose in the cytosol is converted to GDP-fucose by a two-reaction pathway. The first step is carried out by the fucose kinase enzyme, which synthesizes fucose-1-phosphate from fucose with consumption of ATP and liberation of ADP (Ishihara et al., 1968; Park et al., 1998; Richards et al., 1978). GDP-fucose pyrophosphorylase (GFPP) then catalyzes the reversible condensation of fucose-1-phosphate with GTP to form GDP-fucose (Ishihara and Heath, 1968; Pastuszak et al., 1998). Fucose kinase activity has been detected in multiple tissues (Park et al., 1998), and GFPP transcripts and/or biochemical activities have been detected in all tissues tested (except for one immortalized cell line) (Pastuszak et al., 1998), indicating that the fucose salvage pathway is a common, perhaps even universal, feature of mammalian cell types. In analogy to feedback inhibition of GMD, fucose kinase is potently inhibited by GDP-fucose (Park et al., 1998; Richards et al., 1978). There is also evidence that the activity of fucose kinase is regulated in response to assorted stimuli, including stimulation of the brain by dopaminergic pathways and exposure of aortic endothelial cells to nicotine (Hocher et al., 1993; Jork et al., 1984; Ricken et al., 1990).

GDP-fucose produced in the cytosol by either biosynthetic pathway must then enter the Golgi apparatus where it serves as a substrate in the synthesis of fucosylated glycoconjugates by fucosyltransferases. Golgi uptake of GDP-fucose is achieved by a specific transport protein and is coupled with obligatory antiport of GMP into the cytosol (Cacan et al., 1984; Capasso and Hirschberg, 1984; Hirschberg et al., 1998; Puglielli and Hirschberg, 1999; Sommers and Hirschberg, 1982). Golgi preparations from LAD II cells exhibit reduced GDP-fucose transport activity (Lubke et al., 1999; Sturla et al., 2001). This observation recently led to the cloning of a cDNA encoding the Golgi GDP-fucose transporter by complementation of LAD II fibroblasts and the identification of mutations in the corresponding gene in LAD II patients (Lubke et al., 2001; Luhn et al., 2001).

The available evidence indicates that the salvage pathway makes a minor contribution to cellular GDP-fucose pools under normal conditions. Although the amount of fucose in a typical modern human diet has not been well studied, fucose is present in several nonstarch polysaccharides and is a component of glycoproteins and glycolipids from nearly every species. Thus, depending on dietary composition and bioavailability of the fucose in plant or animal glycans, humans and other mammals are likely to ingest variable amounts of fucose. These subjects have not yet been carefully studied. In addition, intestinal microflora synthesize fucosylated glycans that could be catabolized to generate free fucose with subsequent uptake by the colon.

In limited clinical experience with LAD II patients, fucosylated glycan expression is severely impaired in multiple cell types in the absence of fucose supplementation (Etzioni et al., 1992; Frydman et al., 1992; Marquardt et al., 1999a,b). These observations demonstrate that at least in a handful of children fed normal diets, flux through the salvage pathway does not generate cytosolic GDP-fucose concentrations sufficient to overcome the relatively modest defect in transport of GDP-fucose into the Golgi that is characteristic of LAD II cells. Provision of oral fucose, however, restored fucosylation to one LAD II patient (Marquardt et al., 1999b), indicating that the salvage pathway maintains the capacity to generate GDP-fucose concentrations sufficient to overcome defective GDP-fucose import in this disease if supplied with supraphysiological concentrations of fucose. In support of this conclusion, glycoconjugates are undetectable in multiple adult tissues in mice with a targeted mutation of the FX locus unless exogenous fucose is supplied in the chow or water (Smith et al., 2002). These results in fucosylation-deficient humans and mice recapitulate findings with cultured mammalian cell lines with defects in GMD (Reitman et al., 1980; Ripka et al., 1986) or the FX protein (Becker et al., data not published). Disabling the de novo pathway in these cell lines abolishes cell surface fucosylated glycan expression, implying that the amount of fucose and fucosylated glycoconjugates in standard fetal bovine serum–containing cell culture medium is inadequate to correct fucosylation via supply of the salvage pathway. This observation is consistent with the relative paucity of fucosylation of plasma glycoproteins and contrasts with the relatively greater abundance of galactose and N-acetylgalactosamine on such glycoproteins. Such glycoproteins, when endocytosed and catabolized in the lysosome, can restore defective O-glycosylation characteristic of ldlD Chinese hamster ovary cells, a UDP-galactose/UDP-N-acetylgalactosamine 4-epimerase-deficient cell mutant in which UDP-galactose and UDP-N-acetylgalactosamine synthesis is disabled unless circumvented by free galactose (Kingsley et al., 1986).

Other pathways of fucose metabolism in mammalian cells?

Additional pathways for GDP-fucose biosynthesis have not been described in mammalian cells. Bacteria are capable of growth on fucose as the sole carbon and energy source by means of a fucose-inducible operon encoding fucose catabolic enzymes. The steps in this pathway include entry of free fucose into the bacterial cell through a permease protein, isomerization of fucose (an aldose) to form fuculose (a ketose; C 2 is a keto group, whereas C 1 is no longer an alcohol), phosphorylation of fuculose to form fuculose-1-phosphate, and an aldolase reaction to form lactaldehyde and dihydroxyacetone phosphate from fuculose-1-phosphate (Chen et al., 1987; Hooper et al., 1999; Zhu and Lin, 1988). Early investigations of bacterial fucose metabolism during the 1950s proposed the possibility that fucose might be synthesized from two three-carbon units, either by a pathway operating in reverse from the fucose catabolic pathway or by variations on this theme (Huang and Miller, 1958a,b). However, evidence supporting this proposed fucose synthetic pathway has never been reported.

Fucose catabolism by bacteria is well described, varies according to the species, and can be robust enough to allow some bacteria to use fucose as a carbon source (Dahms and Anderson, 1972; Hacking and Lin, 1976). These observations imply that free fucose in the diet, or released in the digestive tract from ingested fucose-containing foods, may be diverted to catabolic pathways before absorption by the digestive tract. The degree to which intestinal bacteria contribute to oral fucose disposition is not understood. In contrast, a catabolic pathway for utilization of free fucose as an energy source has not been identified in mammalian cells. However, in a study involving intravenous administration of [1-14C]fucose to human patients, it was reported that 39% of the injected radioactivity was excreted as 14CO2 (Segal and Topper, 1960), suggesting that fucose could be metabolized to smaller metabolic units. Subsequent work in rats corroborated this finding, but the proportion of administered fucose that was metabolized in this manner was much smaller, with only 1.6% of the intraperitoneally injected [1-14C] fucose appearing as 14CO2 (Bekesi and Winzler, 1967).

In contrast, injection of milligram quantities of free fucose to mice did not lead to formation of glycogen (Shull and Miller, 1960), implying that fucose is not broken down into three-carbon glycogenic intermediates and thus diminishing the likelihood that fucose is catabolized in mammals by a pathway analogous to the bacterial catabolism. These observations contrast with biochemical studies of fucose metabolism in pigs (Nwokoro and Schachter, 1975a,b; Chan et al., 1979). This in vitro work identifies a catabolic pathway in extracts of porcine hepatocytes that can convert 1 mol of fucose to 2 mol of L-lactate (Chan et al., 1979). The three assayable enzyme activities in this pathway are found in the liver and kidney and to a lesser extent in other porcine tissues, but only one of the four is found in rat hepatocytes (Chan et al., 1979). It is not yet known if this catabolic pathway operates in other species, nor is it yet clear if it contributes significantly to fucose metabolism in vivo.

Although alternative pathways for fucose metabolism cannot be excluded, the fact that de novo pathway mutant mice and cell lines are crippled in their ability to express fucosylated glycans suggests that the contribution of any additional fucose synthetic pathways to the cellular GDP-fucose pool must be very small or nonexistent in most cell types of adult mammals. It remains to be determined if additional GDP-fucose biosynthetic pathways are active in specific circumstances during development or differentiation or in specialized mammalian cell types.

  1. John B. Lowe1,2,3,4,5
  1. 2Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, MSRB I, room 3510, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0650, USA
  2. 3Howard Hughes Medical Institute, MSRB I, room 3510, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0650, USA
  3. 4Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0650, USA
  4. 5Life Sciences Institute, MSRB I, room 3510, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0650, USA
  1. 1To whom correspondence should be addressed; e-mail: johnlowe{at}umich.edu or beckerd{at}umich.edu
  • Accepted February 10, 2003.
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  1. Glycobiology 13 (7): 41R-53R. doi: 10.1093/glycob/cwg054 First published online: March 19, 2003
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