Fucose in N-glycans- From Plant to Man

Review

Fucose in N-glycans: from plant to man

Erika Staudacher *, Friedrich Altmann, Iain B.H. Wilson, Leopold Ma«rzInstitut fu«r Chemie, Universita«t fu«r Bodenkultur, Muthgasse 18, A-1190 Vienna, Austria

Received 3 February 1999; received in revised form 6 May 1999; accepted 27 May 1999

Abstract

Fucosylated oligosaccharides occur throughout nature and many of them play a variety of roles in biology, especially in anumber of recognition processes. As reviewed here, much of the recent emphasis in the study of the oligosaccharides inmammals has been on their potential medical importance, particularly in inflammation and cancer. Indeed, changes infucosylation patterns due to different levels of expression of various fucosyltransferases can be used for diagnoses of somediseases and monitoring the success of therapies. In contrast, there are generally at present only limited data on fucosylationin non-mammalian organisms. Here, the state of current knowledge on the fucosylation abilities of plants, insects, snails,lower eukaryotes and prokaryotes will be summarised. ß 1999 Elsevier Science B.V. All rights reserved.

Keywords: Fucosyltransferase; Fucose; Fucosylation; N-glycan; Glycobiology

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

2. Fucosylation of N-glycans in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2172.1. Fertilisation and development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2182.2. Cell adhesion mediated by selectins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2182.3. Fucosylation in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.4. Other fucosylation events related with disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.5. Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

3. Mammalian Fuc-Ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203.1. Human K1,2-Fuc-Ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203.2. Human K1,3/4-Fuc-Ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203.3. Terminal Fuc-Ts of other mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203.4. K1,6-Fucosylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

4. Insects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

0304-4165 / 99 / $ ^ see front matter ß 1999 Elsevier Science B.V. All rights reserved.PII: S 0 3 0 4 - 4 1 6 5 ( 9 9 ) 0 0 1 8 1 - 6

Abbreviations: Fuc, fucose; Gal, galactose; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; Man, mannose; Xyl,xylose; Fuc-T, fucosyltransferase

* Corresponding author. Fax: +43 (1) 36006-6059; E-mail : [email protected]

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5. Snails . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

6. Trematodes and nematodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

7. Amoeba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

8. Fucosylation in other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

9. Prokaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

10. Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

11. Relationships of Fuc-Ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

12. Fucosylation and biotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

13. Future aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

14. Note added in proof . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

1. Introduction

The basic biosynthetic pathway of N-glycans ineukaryotes is a highly conserved process [1,2], butthe microheterogeneity of the glycans depends onthe organism, the tissue and the developmental andphysiological status of the cell by the availability ofprocessing glycosidases and glycosyltransferases aswell as accessibility of the glycans [3]. The improve-ment in methods for glycan analysis [4] and in mo-lecular biology has caused an immense increase inthe amount of knowledge about glycans involved invarious recognition processes and on the correspond-ing glycosyltransferases. One feature that often variesis the number and the type of linkage of fucose (Fuc)residues. Normally, in N-glycans, Fuc is attached inK-linkage to galactose (Gal) in 1,2 or to N-acetylglu-cosamine (GlcNAc) residues in 1,3, 1,4 or 1,6. Directfucosylation of peptides, which is also known, hasbeen reviewed elsewhere [5]. The correlation offucosylation patterns with adhesion events and vari-ous diseases led to intensive investigations on,especially human, fucosyltransferases (Fuc-Ts) andtheir regulation during developmental or pathologi-cal processes. Once the human Fuc-T genes wereanalysed, sequences from other sources could be

identi¢ed. Now, more than 150 entries of completeor partial sequences of Fuc-Ts from prokaryoticas well as eukaryotic origin can be found throughthe internet (e.g. NCBI GenBank: 6 http://www.ncbi.nlm.nih.gov/Entrez/index.htmls or Ex-PASy, Swiss-Prot: 6 http://www.expasy.ch/cgi-bin/sprot-search-fuls ). Since the number of entries israpidly increasing, a printed list would go out ofdate quickly and is therefore omitted here.

Normally, research on non-mammalian organismsis only carried out if these organisms are of somemedical or commercial interest. Therefore, somedata exist on human pathogens, venoms and plantpollen or food allergens. Furthermore, plant and in-sect cells which are potential, or already used, expres-sion systems for the production of recombinant (gly-co)proteins have been studied for their glycosylationabilities. Although a summary of recent literature onfucosylation in eukaryotes generally is given here, weplace particular emphasis on non-mammalian sys-tems.

2. Fucosylation of N-glycans in mammals

In mammalian tissues, Fuc can be linked K1,2 to

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terminal Gals, K1,3 or K1,4 to subterminal GlcNAcresidues of the antennae and K1,6 to the innermostGlcNAc (Fig. 1). Various functions have been, andwill be, found for Fuc residues, especially those dec-orating the outer chains of oligosaccharides. Theyplay an important role in several cell recognitionprocesses ranging from fertilisation and developmentthrough to pathological events and cell death.

2.1. Fertilisation and development

Protein-carbohydrate interactions regulate, at leastin part, the binding of the sperm to the zona pellu-cida [6]. For example, in porcine zona pellucida, anumber of negative-charged, fucosylated N-glycanshave been found to be involved in sperm binding[7^9]. In the bovine and murine systems, the require-ment of a Fuc residue is possible [10,11]. However,whereas the tetrasaccharide epitope FucK1,2-GalL1,3(FucK1,4)GlcNAc- is present in N- and O-glycans of the human zona pellucida, this structurewas not detected on bovine or porcine oligosaccha-rides [12]. This leads to the hypothesis that species-speci¢c glycosylation regulates sperm binding. Thistheory is supported by the fact that human oocytesthat cannot be fertilised in vitro display a slightlyaltered carbohydrate distribution [13]. In addition,Fuc-Ts and their products were identi¢ed on rat epi-didymal spermatozoa where they may also be in-volved in adhesion processes [14,15].

In the course of development, changes in fucosyl-ation activities can be observed in the various tissuesof young animals. A number of changes in fucosyla-tion patterns were found in rats from the day ofbirth, during the suckling period, shortly after wean-

ing, until adult patterns appeared, in£uenced also bythe manipulation of nutritional factors [16^20].

Changes in fucosylation activity occur not only inthe young animal but also in the pregnant mother.The degree of branching and K1,6-fucosylation is in-creased on human glycoprotein hormone K-subunitglycans during the second trimester of pregnancy[21].

2.2. Cell adhesion mediated by selectins

There are much data to indicate that K1,3-fuco-sylated carbohydrates (for abbreviations, see Table1) and their sulfated and sialylated variants act asligands for selectins, a family of adhesion receptors.L-selectin (LAM-1, LECAM-1) is a constitutively ex-pressed lymphocyte homing receptor of most leuko-cytes, while E-selectin (ELAM-1, LECAM-2) is ex-pressed on the cell surface of endothelial cells afteractivation with cytokines and endotoxins and P-se-lectin (GMP-140, PADGEM, LECAM-3) is a rap-idly inducable receptor expressed on the plasmamembrane of endothelial cells and platelets [22^24].The carbohydrate recognition process is involved inseveral acute and chronical in£ammatory disorderssuch as rheumatoid arthritis and skin in£ammation.These medical aspects encouraged basic research in

Table 1Names and structures of acceptors and products of Fuc-Ts

Fig. 1. Typical mammalian complex N-glycans.

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this area. The great number of resulting publicationscan be divided into three groups. (i) Carbohydrateanalysis: elucidation of the preferred ligands of theselectins and the characteristic ligand patterns of spe-ci¢c types of cells, e.g. [25^27]. (ii) Identi¢cation ofthe Fuc-T(s) which are responsible for forming thetypical ligands, in particular the roles of Fuc-T VIand Fuc-T VII are under continuing investigation,e.g. [28^35]. (iii) Attempts to reduce or to inhibitthe binding by modi¢cation of the carbohydrate li-gand or by the construction of inhibitors, e.g. [36^42]. These results could lead to the development ofanti-adhesion therapeutics in the near future.

2.3. Fucosylation in cancer

Protein-linked glycans in cancer cells are generallyhighly branched and often, their oligosaccharidecomposition is altered compared with normal cells.The presence of such tumour-associated carbohy-drates can give information on the potential malig-nity of a tumour and its metastasising potential. Inaddition, such correlations are helpful in the diagno-sis, are of prognostic value and aid the observationof the progress of therapy [43]. The glycans are in-volved in the immunological response of the organ-ism, cell adhesion during metastasis and modulationof the function of proteins [44]. Often, the numberand type of linkage of Fuc and sialic acid residuesare characteristic for several tumours. In parallelwith an increased number of fucosylated glycans,the expression of the corresponding Fuc-Ts is alsoelevated.

In lung carcinoma, the enhanced expression ofFuc-T IV and VII is related to a high metastaticpotential and a poor prognosis [45^47], while in-creased synthesis of sialyl Lex structures by Fuc-TIII is involved in colon cancer metastasis [48,49].Patients who express these structures have a signi¢-cantly poorer disease-free survival rate [50]. Di¡erentreports suggest increased Fuc-T III or Fuc-T V ac-tivities in human intestinal cancers [51^53].

The role of the enzymes responsible for the accu-mulation of K1,2-fucosylated antigens is a matter ofcontroversy. While transfection of poorly tumouro-genic rat colon carcinoma cells with human H-typeK1,2-Fuc-T enabled these cells to form progressivetumours [54], in human colon adenocarcinoma cell

lines, only Se-type K1,2-Fuc-T was expressed [55]. Inaddition, a new K1,2-Fuc-T activity associated withFuc-T III and exhibiting di¡erent substrate-speci¢c-ities was identi¢ed in colon carcinoma cells [56,57].

In hepatocarcinogenesis, the increased level ofK1,6-Fuc-T expression and its products correlate inhumans and rats with tumour development [58,59].However, in chronic hepatitis and liver cirrhosis,K1,6-Fuc-T activity was found also to be increasedcompared with normal liver [60^62]. In patients withneoplastic diseases of the liver, not only fucosylationbut also the degree of branching of the N-glycans ofK-fetoprotein has to be taken into account to providean accurate criterion for tumour identi¢cation[63,64].

Also several other types of carcinomas were foundto exhibit increased fucosylation of surface glycansinvolved in selectin-mediated binding and enhancedexpression of Fuc-Ts. However, the exact mechanismof this up-regulation and the identity of the relevantenzymes is still not clear, antibodies against theseoverexpressed epitopes coupled with cytotoxic agentsare considered as anti-cancer vaccines [65].

2.4. Other fucosylation events related with disease

There are a number of recently published reviewsin which glycosylation in disease is discussed [66^68].Since Fuc is a relevant part of several ligands in-volved in adhesion processes (see above), it is notreally surprising that additional pathological recog-nition events, invasion of viruses, bacteria or para-sites are dependent on fucosylated glycans [69].

While it is possible in the future that genetic ther-apy will enable the correction of defects in the ex-pression of Fuc-Ts, lysosomal fucosidases and syn-thesis of GDP-Fuc, pathological processes where Fucis part of an epitope in an adhesion process may bein£uenced by well-designed and optimally targeteddrugs.

2.5. Apoptosis

Fucosylation also seems to play a role during theprogrammed cell death, apoptosis. Mouse thymo-cytes and P815 cells showed an increased amountof exposed Fuc residues on the cell surface after in-duction of apoptosis by three di¡erent agents, dexa-

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methasone, gliotoxin and thapsigargin [70]. Histolog-ical studies of many tumours and normal tissues re-vealed close correlation of elevated Ley expressionwith the process of apoptosis [71]. In human HAT-29 colon adenocarcinoma cells, strongly enhancedexpression of Lex and slightly enhanced expressionof Ley were observed on the cell surface prior tocell death. The Lex expression correlated with anincreased activity of K1,3-Fuc-T IV [72]. Due to thefact that increased fucosylation was observed in dif-ferent cell types after induction of apoptosis by dif-ferent agents, it seems to be not a signal but one ofthe results of the `program' for cell death.

3. Mammalian Fuc-Ts

3.1. Human K1,2-Fuc-Ts

K1,2-Fuc-Ts catalyse the transfer of a Fuc residueinto K1,2-linkage to a terminal Gal residue of N- orO-glycans, a necessary step in the formation of ABOblood group antigens [73]. An additional Fuc K1,3-or K1,4-linked to the penultimate GlcNAc or sialicacid K2,3- or K2,6-linked to the Gal normally blocksthe transfer. In human tissues, two enzymes sharingthis speci¢city have been found (reviewed in [74]).The H-type enzyme is found in haematopoietic cellsand plasma and prefers type 2 acceptor substrates.However, it fucosylates also phenyl-L-D-galactosides.The Se-type enzyme occurs in secretory £uids andtissues of ABO blood group secretors and prefersboth type 1 and type 3 acceptors [75]. Both enzymeshave been cloned [76,77] and their genes (FUT1 andFUT2, respectively) were found to be located close toeach other on human chromosome 19.

Individuals with mutations in one of the two genesfail to express or have reduced expression of A, Band H antigens on the surface of di¡erent tissues (H-and Se-enzyme are de¢cient in variants of the so-called Bombay phenotype) [78^81]. These pheno-types have a relatively high frequency in some pop-ulations and apparently do not exhibit any harmfule¡ects. Therefore, they can be used for inheritancestudies.

A third type of K1,2-Fuc-T associated with theK1,4 activity was found in several human carcinomatissues and co-puri¢ed with K1,4-Fuc-T from colon

carcinoma Colo 205 cells. The enzyme reveals abroad speci¢city combined with a high e¤ciencyand may be potentially involved in malignancy [56].

3.2. Human K1,3/4-Fuc-Ts

Five human K1,3-Fuc-Ts (Fuc-T III^VII) havebeen cloned [82^90] and are a family of closely re-lated membrane bound glycosyltransferases. Theirgenes (FUT3^7) are highly homologous. Three ofthem (FUT3, FUT5 and FUT6) are located very closeto each other in a cluster on chromosome 19p13.3[91]. They are distinguishable by acceptor speci¢cityand biochemical as well as kinetic parameters. Theirexpression depends on the tissue and the develop-mental and physiological status of the cell. Fuc-TIII is noteworthy one of the rarely occurring glyco-syltransferases that catalyse the formation of twodi¡erent glycosidic linkages, since it acts as both anK1,3- and an K1,4-Fuc-T depending on the substrate.Details on all of these enzymes can be found in anumber of reviews which have been published in re-cent years [92^95].

In human tissues, normally, a mixture of severalactivities is responsible for the observed fucosylation.With genetic methods, individual recombinant en-zymes were characterised in various systems, freefrom interfering activities [96^103]. The identi¢cationof these genes and modern methods of molecularbiology make it possible to evaluate the distributionof single enzymes in various tissues or to study theircontribution to developmental processes [104^108].Furthermore, site-directed mutagenesis of these en-zymes has been performed to ascertain the roles ofcertain amino acid residues in binding of GDP-Fuc,acceptor speci¢city, kinetic parameters or inhibitorsensitivity [109^118]. Such results may allow for thefuture development of genetic therapies for patientswith defects in their fucosylation potentials. Today,the information can help to optimise Fuc-Ts for theproduction and modi¢cation of oligosaccharides nec-essary in research or therapy.

3.3. Terminal Fuc-Ts of other mammals

Recently, a number of Fuc-T genes from othermammals have been cloned by homology to the hu-man Fuc-Ts. This reveals information on the evolu-

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tion of these enzymes. For instance, the chimpanzeepossesses FUT3, FUT5 and FUT6 genes with about98% sequence homology to the corresponding humangenes [119]. In contrast, there is a single bovine gene,corresponding to the human gene cluster FUT3-FUT5-FUT6, whose gene product shares more than60% amino acid sequence identity with all three ofthe human enzymes [120].

In rodents, a Fuc-T IV has been cloned from mice[121,122] and rat [123] while Fuc-T VII has only beencloned from mice [124]. Furthermore, a novel murineK1,3-Fuc-T (mFuc-T IX) was cloned and its tran-scripts were detected in mouse brain, kidney andneuronal cells. The enzyme shows below 50% homol-ogy to all other known Fuc-Ts, thus it does notbelong to any subfamily of the known K1,3-Fuc-Ts.The substrate speci¢city of mouse Fuc-T IX is sim-ilar to human Fuc-T IV and forms Lex epitopes, butnot sialylated Lex structures. The enzyme is consid-ered to participate in the Lex synthesis in neurons ofthe brain [125]. Also in some rat cells, an K1,4-Fuc-Tactivity has been detected [126,127], thus at least oneadditional enzyme with some similarities to Fuc-T IIIawaits cloning of its gene.

Chinese hamster ovary (CHO) cells, a frequentlyused expression system for glycosyltransferases, wereinitially thought not to express any K1,3-Fuc-T ac-tivity. However, following mutagenesis or transfec-tion with large amounts of foreign DNA, mutantsthat express K1,3-Fuc-T activity have been obtained[128,129]. Also after the transfection of a humanK1,3-Fuc-T gene, false positive clones from the acti-vation of an endogenous enzyme complicated theidenti¢cation of the transfectants [130]. Thus, CHOcells contain Fuc-T gene(s) that are normally quies-cent, but can be activated by mutational events. Inanother frequently used cell line, monkey kidneyCOS-7 cells, three di¡erent endogenous Fuc-Tswere identi¢ed, one revealing a similar acceptor spe-ci¢city as Fuc-T IV [131].

Rabbits contain three di¡erent active K1,2-Fuc-Ts.One of them (RFT-I) shows more than 80% identitywith the human H-type enzyme. Both other enzymes(RFT-II, RFT-III) are highly homologous to eachother. Their acceptor speci¢city, preference of type1 and type 3 acceptors, suggests that they are puta-tive Se-type enzymes [132,133]. All rabbit Fuc-Ts aredevelopmentally regulated [134].

Rats and mice contain both analogues to humanK1,2-Fuc-Ts [135,136]. From pigs, a H-type K1,2-Fuc-T has been cloned [137] and a partial aminoacid sequence of a porcine Se-type homologous en-zyme was determined from submaxillary gland [138].

3.4. K1,6-Fucosylation

Fuc in K1,6-linkage to the asparagine-linkedGlcNAc residue of a N-glycan is a typical mamma-lian feature [139]. In vivo, K1,6-fucosylation protectsglycans in humans against hydrolysis by glycoaspar-aginase [140] and is one necessary requirement forpolysialylation [141]. However, K1,6-fucosylation ofthe innermost GlcNAc residue has also been foundin insects and snails (see later), but so far never inplants. This type of enzyme was ¢rst extensivelycharacterised, around 20 years ago, in Harry Schach-ter's laboratory from rat and porcine liver micro-somes [142,143]. About 10 years later, the ¢rst puri-¢cation, from cultured human skin ¢broblasts, wasreported [144]. More recently, the enzyme was clonedfrom porcine brain [145] and a human gastric cancercell line (MKN45) [146]. A puri¢ed K1,6-Fuc-T fromhuman platelets shares acceptor speci¢city and bio-chemical parameters, such as a lack of necessity forcations, with the cloned ones [147].

All these K1,6-Fuc-T activities require an unsub-stituted GlcNAc residue in the C2 position to themannose (Man) of the K1,3-antennae of the N-glycanfor the transfer. However, the presence of K1,6-Fucon structures lacking the GlcNAc on the K1,3-branchhas been reported in some cases [148^151]. This mayeither be due to alternative Fuc-T activities, a resid-ual activity of Fuc-T towards structures lacking thenon-reducing terminal GlcNAc, or, akin to the casein plants and insects, a processing L-hexosaminidase[152,153].

A bisecting GlcNAc residue, linked L1,4 to the L-Man of the core [154], or the prior addition of anK1,3-linked Fuc to the innermost GlcNAc are`NOGO' signals for transfer [155]. Furthermore, theenzyme is not able to catalyse a linkage if a chemicalalteration of the GlcNAc occurred, for example by£uorescent labelling. Therefore, new methods had tobe developed to show a speci¢c incorporation in vi-tro [156,157].

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4. Insects

Structural analysis of insect N-glycans reveals thatthey can be fucosylated in three possible ways (Fig.2). (i) Fucosylation in K1,6-linkage to the innermostGlcNAc as found in mammals, (ii) in K1,3-linkageagain to the proximal GlcNAc residue as in plantsand (iii) the formation of N-acetylgalactosamine(GalNAc)L1,4(FucK1,3)GlcNAcL1,2 (K1,3-fucosyl-ated LacdiNAc). A selection of N-glycans from hon-eybee (Apis mellifera) venom phospholipase A2

shows all three of these modi¢cations [158]. The ¢rstcore-difucosylated N-glycan to be described wasfrom this source [159]. Subsequently, such difucosyl-ation was also found in other honeybee venom gly-coproteins [160], lepidopteran cells [161], on oligosac-charides of a trematode [162] and a nematode [163].Apart from honeybee (A. mellifera) venom glycopro-teins [158,160], the K1,3-fucosylated `LacdiNAc'structure has only been found rarely in other organ-isms: in bovine pro-opiomelanocortin [164], humanurokinase [165], recombinant human protein C ex-pressed in human kidney cells [166], a schistosome[167] and a pit viper [168].

While no information exists on the transferase re-sponsible for fucosylating the terminal antennae, thefucosylation activities required for both types of in-sect core fucosylation are characterised in terms oftheir acceptor speci¢city. Both, the K1,6- and theK1,3-Fuc-Ts require an unsubstituted GlcNAc resi-due linked to the K1,3-antennae, similar to the sub-strate requirements of mammalian K1,6-Fuc-Ts (seeabove) [169]. The biosynthesis of core-difucosylatedglycans proceeds in a strict order: the K1,3-Fuc-T isable to convert non-fucosylated as well as K1,6-fuco-sylated acceptor substrates [170]. However, the K1,6-

Fuc-T is inhibited by prior K1,3-fucosylation of theinner GlcNAc, thus, in biosynthesis of difucosylatedglycans, the K1,6-Fuc-T must act before the K1,3-Fuc-T [155]. For further details on insect glycosyla-tion and their use as hosts for the expression of re-combinant glycoproteins, the reader is referred toother reviews from this laboratory [171^174].

5. Snails

The ¢rst analysis of a snail N-glycan was carriedout on Helix pomatia K-hemocyanin by van Kuik etal. in 1985 (Fig. 3a) [175]. The major low molecularweight N-glycan of this protein was found to be aMan3GlcNAc2-core with a Fuc K1,6-linked to theinner GlcNAc and a L1,2-linked xylose (Xyl) at-tached to the L-Man residue. It was the ¢rst timethat Xyl was found as a component of an animalN-glycan. Further studies on the K-hemocyanins ofH. pomatia and Lymnea stagnalis con¢rmed L1,2-linked Xyl as a typical component of snail N-glycans.While fucosylation in H. pomatia is restricted to anK1,6-Fuc to the inner core, L. stagnalis exhibits K1,2-linked Fucs to terminal Gal residues (Fig. 3b)[176,177]. The K1,2-Fuc-T responsible for these unitsprefers GalL1,3GalNAc over type 1 or type 2 accep-tors and is therefore di¡erent from other K1,2-Fuc-Ts described. Furthermore, in connective tissue aswell as albumen glands of L. stagnalis, an K1,3-Fuc-T activity was found which utilises type 2 ac-ceptors to form Lex structures [178]. However, no

Fig. 3. Fucosylated N-glycans from snails. (a) H. pomatia [175],(b) L. stagnalis [176].

Fig. 2. Fucosylated insect N-glycans.

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corresponding K1,3-fucosylated glycans have beendetected so far. Preliminary data from our own lab-oratory on Arionta species would suggest that abroader, non-protein-speci¢c approach for the inves-tigation of the snail `glycome' will lead to the discov-ery of unexpected, perhaps so far unknown struc-tures.

6. Trematodes and nematodes

During the past years, the investigation of hel-minth glycosylation revealed several remarkablenew structures presumably playing a role in host^parasite interactions. They may be promising targetswhich can be used for vaccine development.

For example, blood £ukes of the genus Schistoso-ma are helminthic parasites causing schistosomiasis,a vascular parasitic disease a¥icting millions of peo-ple world-wide. This parasite has a complex life cycleinvolving an invertebrate (fresh water snail) and avertebrate host. A developmentally regulated expres-sion of Lex antigens was detected in O- and N-gly-cans of adult worms, these glycans induce changes inimmune cell populations and the production of cyto-lytic autoantibodies in the vertebrate hosts[167,179,180]. The corresponding K1,3-Fuc-T hasan acceptor speci¢city and biochemical properties re-sembling those of human Fuc-T IV [181]. In additionto terminal Lex determinants, the glycoproteins ofSchistosoma mansoni and Schistosoma japonicumeggs contain K1,3- and K1,6-core-fucosylated aswell as K1,3/K1,6-difucosylated N-glycans with orwithout a L1,2-linked Xyl residue (Fig. 4a) [162].Thus far, this is the only example of K1,3/K1,6-difu-cosylated N-glycans carrying Xyl residues.

The cercariae of the avian schistosome Trichobil-harzia ocellata contain an K1,2- and an K1,3-Fuc-Tinvolved in the biosynthesis of the FucK1,2-FucK1,3GlcNAc element occurring on the O-glycansand glycosphingolipids of this organism [182^184].The acceptor speci¢city of the K1,3-Fuc-T resembledin vitro human Fuc-Ts V and VI, showing a prefer-ence for structures based on type 2 chains, whereastype 1 chains were only poor acceptors. The K1,2-Fuc-T described is the ¢rst Fuc-T identi¢ed transfer-ring Fuc from GDP-Fuc to another Fuc residue

forming the unit FucK1,2Fuc. Therefore, no compar-ison with other K1,2-Fuc-Ts is possible.

None of the nematodes (Diro¢laria immitis, Hae-monchus contortus, Caenorhabditis elegans) or othertrematodes (Fasciola hepatica) investigated werefound to express glycans containing Lex or sialylatedLex determinants, but several of the glycoproteinsbound to Lotus tetragonolobus agglutinin, which isspeci¢c for FucK1,3GlcNAc structures [185].

Although C. elegans and H. contortus apparentlydo not express Lex antigens, K1,3-Fuc-Ts capable ofthis type of fucosylation have been identi¢ed in theirextracts and were cloned [186,187]. The C. elegansenzyme (CEFT-1) expressed in COS-7 cells synthe-sised Lex but not sialylated Lex units. Besides thecloned enzyme, another K1,3-Fuc-T activity, whichcould also fucosylate sialylated acceptors, and anK1,2-Fuc-T activity speci¢c for type 1 chains weredetected [186]. The H. contortus enzyme has proper-ties which resemble those of the cloned C. elegansenzyme except that it also can utilise sialylated ac-ceptors [187]. However, due to the lack of a L1,4-galactosyltransferase, the biological function of theseenzymes is hypothesised to be in the synthesis ofterminal FucK1,3GlcNAc- and K1,3-fucosylated Lac-diNAc structures.

Furthermore, a unique type of fucosylation hasbeen found in H. contortus : three Fucs are attachedto the inner core of the N-glycan. Two in K1,3 andK1,6 position of the proximal GlcNAc, the third onein K1,3 position of the distal GlcNAc of the chito-biose unit (Fig. 4b) [163].

Fig. 4. Fucosylated N-glycans of helminths. (a) S. mansoni[162], (b) H. contortus [163].

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7. Amoeba

In the slime mold Dictyostelium discoideum, a hap-loid amoeba, multiple types of fucosylation occur.Fucosylation has been shown to be essential for theformation and proteolytic protection of spores andfor their e¡ective germination. Using speci¢c anti-bodies, Fuc and phosphoFuc O-linked to serineand K1,3- as well as K1,6-core-fucosylated N-glycanswere detected [188^190]. The Fuc-Ts acting on the N-glycans are developmentally regulated. Core K1,3-Fuc-T activity was exclusively found during develop-ment, whereas K1,6-Fuc-T activity reached its max-imum during growth and decreased during develop-ment [190].

Furthermore, an K1,2-Fuc-T activity utilising type1 oligosaccharides in vitro was found in the cytosolof D. discoideum [191,192]. The substrate speci¢cityof this enzyme resembles the human Se-type K1,2-Fuc-T but its acceptors in vivo are the Xyl andGal containing O-glycans of a highly conserved fu-coprotein (FP21). The fucosylation of this proteinoccurs in the cytosol, which explains the unusuallocation and the absence of a transmembrane do-main in the Fuc-T [193].

8. Fucosylation in other animals

So far, the only bird where fucosylation has beeninvestigated is chicken. An K1,3-Fuc-T related to hu-man Fuc-T IV with about 50% homology to thehuman and mouse enzymes was cloned and charac-terised [194] and organ-speci¢c distribution of K1,6-fucosylation of transferrin was detected [195].

N-glycans puri¢ed from the ovarian £uid of rain-bow trout contain K1,6-linked Fuc linked to the in-ner core as well as polysialic acid-modi¢ed Lex deter-minants on the antennae [196]. Recently, two newK1,3-Fuc-T genes have been detected in the zebra¢shgenome. They synthesise Lex structures, but althoughthey show signi¢cant homology in general to otherK1,3-Fuc-Ts, they are not speci¢cally related to anysingle one (S. Natsuka, N. Kageyama, S. Hase, Int.Carbohydrate Symposium 1998, San Diego, CA,USA).

A non-terminal Fuc occurring in the novelGalL1,4Fuc unit linked K1,6 to the inner GlcNAc

was found on a N-glycan from octopus rhodopsin(Fig. 5) [197]. However, this is the only examplefor such a structure. In general, there are little dataon invertebrate glycoproteins, thus it remains possi-ble that this structure will be found elsewhere. Inamphibians, highly fucosylated O-glycans are usual,which contain various non-terminal Fucs. There,they are perhaps involved in the fertilisation processand may be a valuable model to examine changes inO-linked carbohydrate structures during evolution[198].

The venom of the funnel web spider (Agelenopsisaperta) contains K1,6-fucosylated N-glycans [151]and the venom of a pit viper (Bothrops moojeni) con-tains glycoproteins carrying a Fuc linked K1,6 to thecore and an K1,3-linked Fuc attached to GlcNAcresidues of the antennae [168].

9. Prokaryotes

The ¢rst, and so far the only, prokaryote revealinga fucosylated oligosaccharide related to those ofhigher organisms is Helicobacter pylori. It is a humanpathogenic Gram-negative bacterium causing gastri-tis, gastric and duodenal ulcer and gastric adenocar-cinoma. It may colonise the human gastric mucosaby adhesion to Leb antigens of gastric epithelial cells[199]. Fucosylated antigens play an important role inthe course of its infection. The Lex and Ley determi-nants expressed on lipopolysaccharides of the micro-organism mimic human cell surface glycoconjugatesand induce autoantibodies, which may result in thechanges revealed in the gastric mucosa by immuno-histopathology [200,201]. Cloning of the H. pyloriK1,3-Fuc-T responsible for forming the Lex determi-nant and comparing it with mammalian K1,3-Fuc-Tsrevealed only a short highly conserved region. Fur-

Fig. 5. N-glycan from octopus rhodopsin [197].

BBAGEN 24929 17-11-99


thermore, the enzyme lacks the transmembrane re-gion typical for eukaryotic Fuc-Ts [202,203].

A novel Fuc-T activity was found in various soilbacteria (Bradyrhizobium japonicum, Azorhizobiumcaulinodans, Rhizobium loti). This bacterial nodula-tion protein (NodZ) fucosylates in vivo lipochinin.However, in vitro, also oligosaccharides with aGlcNAc residue at the reducing terminus and Lex

units are substrates [204].

10. Plants

A typical feature of plant N-glycans is the XylL1,2-linked to the L-Man residue and an K1,3-linkedFuc to the inner GlcNAc of the core (Fig. 6). Pres-ently, peptide-N4-(N-acetyl-L-glucosaminyl) aspara-gine amidase A from almond emulsin is the onlyN-glycanase commercially available able to cleaveK1,3-core-fucosylated N-glycans from the peptidebackbone [205]. Since its introduction as a tool forthe analysis of plant glycans, it was found that thiskind of core K1,3-fucosylation is widespread inplants. This is of particular interest since plant car-bohydrates are involved in pollen and food allergy.Both K1,3-linked Fuc and the Xyl form antigenicepitopes which account for some IgE cross-reactionsbetween various plant, insect and mollusk extracts[206^208]. However, the K1,3-Fuc linked to the in-nermost GlcNAc seems to be the most importantresidue in the epitope [208,209].

A core K1,3-Fuc-T was puri¢ed from germinatingmung bean seedlings. The enzyme requires, similarlyto core K1,6-Fuc-Ts, the presence of an unsubstitutedGlcNAc residue linked to the K1,3-antenna of the

glycan. Neither type 1 nor type 2 structures serveas acceptor substrates for the enzyme [210].

Another Fuc-T activity converting type 1 accep-tors to Lea structures was also detected in mungbeans [211]. The corresponding structures with Lea

units on their antennae were identi¢ed from laccase,puri¢ed from the culture medium of sycamore cells(Acer pseudoplatanus L.) and from a peroxidase, pu-ri¢ed from the culture medium of Vaccinium myrtil-lus L. cells [212,213]. Using anti-plant Lewis antibod-ies, Lea epitopes were detected in protein extracts ofvarious monocotyledonous, dicotyledonous andgymnosperm plants, which suggests that the Lea epi-tope is more widely distributed than previously ex-pected [212]. For an extensive review on N-glycanbiosynthesis in plants, see Lerouge et al. [214].

11. Relationships of Fuc-Ts

The detailed knowledge of eight human Fuc-Tgenes and an increasing number of homologuesfrom other species has prompted various comparisonstudies. Alignment studies for the identi¢cation ofhighly conserved functional regions revealed thatmammalian K1,2- and K1,3-Fuc-Ts have a similarpredicted folding consisting of alternate K-helicesand L-strands [215]. In a further study, a nucleotidebinding region near the C-terminus and an acceptorbinding region near the N-terminus were assigned forprokaryotic as well as eukaryotic enzymes [216]. Fur-thermore, homology studies gave the opportunity toexamine the evolution of Fuc-Ts by the creation of aphylogenetic tree [119,217]. A recently publishedstudy on the alignment of 78 Fuc-T protein sequen-ces from vertebrates, invertebrates and bacteria sup-ports the model that Fuc-Ts evolved from one, orperhaps two, hypothetical ancestor gene(s), followedby duplications and subsequent divergence [218].

12. Fucosylation and biotechnology

The glycosylation potentials of insect cells are ofpharmaceutical interest. Due to their advantage interms of costs as well as of biosafety, lepidopteraninsect cell lines, mainly Spodoptera frugiperda, areused for the baculovirus-mediated expression of re-Fig. 6. Plant N-glycans.

BBAGEN 24929 17-11-99


combinant proteins. Due to various factors, it is de-sirable to achieve a glycosylation pattern as muchalike to the mammalian pattern as possible. In par-ticular non-mammalian features, such as the presenceof the plant-like K1,3-linked Fuc residue on the innerGlcNAc, which is highly immunogenic [209], shouldbe avoided. The same problem has to be consideredwhen using plant cells or plants for the production ofpharmaceuticals.

Enzymatic synthesis and modi¢cation of oligosac-charides are very speci¢c ways to produce well-de-¢ned glycans for biochemical and medical research(e.g. selectin binding or allergenicity studies) [219].All cloned human Fuc-Ts have been used towardsthis end, e.g. [220^223]. In particular Fuc-T III hasbeen expressed in various systems, including themethylotrophic yeast Pichia pastoris [224], and iswidely used for the synthesis of natural and non-nat-ural glycans, e.g. [225^228].

Another application for glycosyltranferases is theiruse for in vivo modulation of carbohydrate epitopes.Mammals, except humans and old world monkeys,express GalK1,3Gal units on glycans of their cellsurfaces. Therefore, xenotransplantation of porcineorgans to humans would immediately induce the pro-duction of antibodies against this epitope, with thesubsequent activation of the complement system. Be-sides the knockout of the porcine K1,3-galactosyl-transferase, the expression of an additional K1,2-Fuc-T is a promising way to modify the carbohy-drates into non-immunogenic structures. The newlyintroduced K1,2-Fuc-T co-localises with the K1,3-gal-actosyltransferase and competes for the same sub-strate. Also the K1,2-fucosylation is a `NOGO' signalfor K1,3-galactosylation [229^234]. However, only acombination of more than one method, for examplethe co-expression of K1,2-Fuc-T and an K-galactosi-dase, e¡ectively reduces the expression of K-Gal tonegligible levels [235].

13. Future aspects

As discussed in the review, fucosylated structureshave proven to be involved in a number of intercel-lular recognition events, but the picture is still farfrom clear. Further attempts have to be made toelucidate changes of the glycosylation patterns dur-

ing pathological processes in order to take advantageof unusual structures for site-speci¢c drug targeting.

Interspecies interactions can also be a¡ected byfucosylation of oligosaccharides. Not only host-para-site interactions should be considered, but also thepossible use of glycoprotein therapeutics derivedfrom non-mammalian systems. Indeed, the increasinguse of cell culture for the production of recombinantglycoproteins for therapeutic purposes forces indus-try to establish easier and cheaper systems, but careshould be taken that the glycans of the proteins pro-duced are similar to those of the natural counter-parts. The knowledge of glycosyltransferase genesallows for the modi¢cation of glycans in vivo bythe additional expression of speci¢c enzymes or byknockout of endogenous enzymes. Genetic engineer-ing of whole mammals which secrete the desiredproduct with their milk or are a potential source oforgans for xenotransplantation may prove a majorpart of the future of biotechnology in this area.

14. Note added in proof

Recently, a sixth K1,3-Fuc-T (Fuc-T IX) has beenidenti¢ed, which reveals high homology to the mouseFuk-T IX [236]. Furthermore, the ¢rst K1,3-Fuc-Tcatalysing the transfer of Fuc into K1,3-linkage tothe innermost GlcNAc-residue of a N-glycan wascloned from mung beans and expressed in Sf 21 in-sect cells. Only one of its four exons exhibits signi¢-cant homology to the known animal and bacterialK1,3/4-Fuc-Ts [237].

Acknowledgements

Research from our laboratory cited in this reviewwas supported by the Fonds zur Fo«rderung der wis-senschaftlichen Forschung (P 10611 GEN and P12552 MOB) and by the Oë sterreichische Hochschul-jubila«umsstiftung.

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Fucose in N-glycans- From Plant to Man

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