Glycobiology Advance Access originally published online on October 15, 2007
Glycobiology 2007 17(12):1321-1332; doi:10.1093/glycob/cwm106
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Changes of Serum Glycans During Sepsis and Acute Pancreatitis
3 Department of Biochemistry and Molecular Biology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia
4 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K
1 To whom correspondence should be addressed: Tel: +385 1 481 8757; Fax: +385 1 4856 201; e-mail: glauc{at}pharma.hr; glauc{at}public.srce.hr.
Received on May 11, 2007; revised on August 28, 2007; accepted on September 27, 2007
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Abstract |
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 Top Abstract IntroductionResultsDiscussionMaterials and methodsFundingConflict of interest statementGlycan structuresReferences |
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Acute inflammatory response is a complex process associated with the production of both pro- and anti-inflammatory mediators. Although it is generally considered to be a single homeostatic mechanism, there are differences associated with the nature and the site of inflammation. We examined the changes of N-linked glycans released from the serum of a patient with sepsis and a patient with acute pancreatitis during the first eight days of the disease. Sera were taken from patients at the time of reporting to hospital and then three more times. The blood from a healthy individual was drawn on one occasion only. Glycans were released using N-glycosidase F and were subjected to normal phase and weak anion exchange high-performance liquid chromatography, exoglycosidase digestions, and mass spectrometry. The levels of identified structures have been followed through the course of disease and compared to the control levels. Changes in serum glycans were found to occur very early in acute inflammation. The most prominent differences include the increase in ratio of outer arm to core fucose, increase in the amount of tetrasialylated structures, changes in the levels of mannose structures, and in the degree of branching. The relative proportions of different glycans changed daily and some differences were also observed between sepsis and pancreatitis, probably reflecting that in these two conditions, the acute phase response is triggered by a different stimulus that is associated with different patterns of production of cytokines.
Key words: glycosylation / pancreatitis / sepsis / serum glycan structures
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Introduction |
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TopAbstractIntroductionResultsDiscussionMaterials and methodsFundingConflict of interest statementGlycan structuresReferences |
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Inflammatory response is a sequence of cellular and molecular events that occur as a reaction to different stimuli such as infection or tissue damage. However, differences in patterns of mediator production (cytokines, prostaglandins, and leukotrienes) in the acute phase response occur in different pathophysiological conditions depending on the nature and the site of inflammation (Gabay and Kushner 1999
). Changes in glycosylation during inflammation have been demonstrated in animal models (Piagnerelli et al. 2005) and in some individual human acute-phase proteins. Changed oligosaccharide branching and increased sialylation of 
-1 acid glycoprotein (van Dijk et al. 1995; Van Dijk et al. 1998) and altered galactosylation of IgG in different inflammatory diseases (Bond et al. 1997) are prominent examples.
Sepsis is a clinical syndrome, which is a result of systemic response to an infection. Since the majority of pathophysiological events during sepsis result from overreaction or uncontrolled inflammatory response, any contribution to the understanding of these processes is important. On the contrary, acute pancreatitis involves a systemic inflammatory response, but without any bacterial infection during the first few days of the disease. It is an inflammatory disease of the pancreatic tissue caused by the activation of enzymes within the pancreas. Early diagnosis of pancreatitis is important, since prompt treatment can reduce the risk of later complications. Unfortunately, at the moment, there are no reliable prognostic markers that could predict the course of this potentially life-threatening disease. Despite the widely accepted fact that glycosylation is essential in the process of inflammation (Lowe 2003), studies of glycosylation changes in sepsis are scarce (Piagnerelli et al. 2005), while glycosylation changes in pancreatitis have not been addressed so far.
The changes in glycan structures during a disease are exceedingly complex and poorly understood processes that involve changes in the expression of glycosyltransferases, their intracellular localization and stability, the availability and transport of activated sugar nucleotides as well as intracellular trafficking of glycoprotein acceptors. In this preliminary study, which was aimed to contribute to the understanding of sepsis and acute pancreatitis, we identified and quantified the major N-linked glycans structures from the serum glycoproteins of patients with these two conditions during the first eight days of the disease, and compared this with the glycans present in normal serum glycoproteins.
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Results |
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Glycan profiles of the whole serum
The N-linked glycans were released from sequentially taken sera of a septic patient and a patient with acute pancreatitis as well as from a healthy individual. The normal-phase high-performance liquid chromatography (NP-HPLC) profiles of patients through the first eight days of disease, as well as the glycan profile from the healthy individual are shown in Figure 1. The structures of the glycans in each peak were identified by combinations of exoglycosidase digestions, chromatographic (NP-HPLC and weak anion exchange (WAX)-HPLC), and mass spectrometric techniques. The NP-HPLC and WAX-HPLC in combination with the exoglycosidase digestions enabled identification and quantification of the intact (sialylated) compounds, including those that coelute in the undigested profile. Quantifications of structures in chromatographic data are expressed as percentage of all the integrated peaks. Mass spectrometric techniques, which were performed on desialylated and unlabeled glycans, complemented the chromatographic data and provided details such as the branching pattern of the triantennary glycans (see legend to Figure 2 for details). Glycans in the major peaks from the HPLC profiles, identified by combination of all the techniques mentioned, are listed in Table I together with the relative percentages. These structures are consistent with those already reported in healthy individuals (Royle et al. submitted) and pool of normal serum. Table II lists the structures of the glycans that were identified by mass spectrometry (MS) techniques, and Figure 3 shows the matrix-assisted laser desorption/ionization (MALDI) profiles of the desialylated glycans taken on Day 8 of disease compared with that from the control patient.
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The analysis of the glycan profiles from patients with acute pancreatitis and sepsis identified several deviations from the healthy profile, as well as changes that occurred during the course of the disease. The most obvious and persistent changes during the first eight days of both conditions were changes in peaks numbered 20 to 26 (Figure 1), identified as being trisialylated and tetrasialylated structures with and without sialyl Lewis x.
Changes in the sialyl Lewis X structures
The changes in trisialylated structures in glycan profiles were persistent in both diseases throughout the studied period. NP-HPLC analysis of trisialylated glycans isolated by WAX-HPLC (Figure 4) showed that the amount of the trisialylated glycan A3G3S3, decreased relative to the amount of the fucosylated A3FG3S3 (sialyl Lewis X) during the period studied, particularly in sepsis. The nonfucosylated form decreased in sepsis from 5.4 to 3.4% in the total glycan pool and in pancreatitis, it decreases from 6.5 to 5.5%, whilst in the healthy control, this fraction represented 8% of the total glycan pool. The fucosylated sialyl Lewis X form increased in sepsis from 6.6 to 6.8%, while in pancretitis, this increase was more expressed at 6.0 to 9.7% of the total glycan pool, compared to 6% in the control (see Table I).
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An HPLC and exoglycosidase sequencing showed that the A3FG3S3 structure digested with almond meal
-fucosidase (AMF) that removes fucose 1–3 or 1–4 linked to GlcNAc and that the galactose on this GlcNAc was removed by ß1–4 galactosidase, indicating that this was a Lewis X rather than a Lewis A structure. The outer-arm fucosylation was also found by negative ion MS/MS analysis (Figure 2E) on desialylated monofucosylated triantennary glycans. The location of the non-core fucose was shown to be on a GlcNAc residue by the absence of a C1 ion corresponding to Gal-Fuc in the MS/MS analysis. The negative ion MS/MS showed the presence of both core and outer-arm fucosylated structures. The relative percentage of the core to antenna-mono-fucosylated triantennary glycans, as measured by the ratio of the 2,4AR ions in the negative ion MS/MS spectrum was 34% antenna and 66% core of the control sample, whereas in the sepsis Day 1 and Day 8 samples, the amount of antenna-fucosylated glycans rose to 52% and 63% for the two days respectively. In pancreatitis, the relative amount of antenna-fucosylated to core fucosylated triantennary glycan rose to 78% on Day 2 and 85% on Day 8. This shows a clear increase in the Lewis X structure relative to the core fucosylated structure with time in both diseases.
Changes in tetrasialylated structures
From the HPLC profiles shown in Figure 1, it is evident that the tetrasialylated structures were elevated compared to the control profile and that the amounts of these structures in the whole glycan pool changed during the course of both diseases. The changes observed were additionally analyzed by NP-HPLC analysis of the tetrasialylated fraction obtained from WAX HPLC, which revealed an increase in outer-arm fucosylated structures over the nonfucosylated ones (Figure 5).
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The negative ion MS/MS of the desialylated monofucosylated tetra-antennary showed that 54% of the fucose was outer arm in the control sample as compared to sepsis samples at Day 1 (75%) and Day 8 (86%), and 92% in both of the pancreatitis samples. This also suggests a move to the Lewis X structure on tetra-antennary structures during the course of disease.
The presence of an outer-arm fucosylation on disialylated biantennary structures was difficult to measure quantitatively due to it low abundance. However, negative ion MS/MS (ratio of the 2,4AR ions) analysis of the disialylated samples detected a trace of the outer-arm fucosylated biantennary glycan present in the control and sepsis Day 1 sample (about 2% of the fucosylated biantennary structures) that rose to about 7% on sepsis Day 8. The amount of antenna-fucosylated biantennary glycans in the pancreatitis samples appeared to be somewhat higher, reaching approximately 10% on Days 2 and 8. The fragmentation pattern showed that the fucose was mainly substituted in the 6-antenna (shifts in the D and [D-18]– ions).
Changes in total fucose
The changes in fucose levels through the course of disease were also seen when we analyzed all the fucose-containing glycans after exoglycosidase digestions (sialidase from Arthrobacter ureafaciens (ABS) + ß-galactosidase from S. pneumoniae (SPG)) or (ABS+SPG+AMF) of the whole glycan pools. Both conditions showed increase in the outer arm fucosylation (sepsis 
50% difference between Day 1 and Day 8, pancreatitis 30% increase), while core fucosylation decreased in both conditions (15%).
Changes in oligomannose structures
The NP-HPLC profile of neutral fractions (prepared by WAX HPLC) showed peaks identified as being oligomannose structures (peaks Man5, Man6, Man7, Man8, and Man9) by digestion with Jack Bean mannosidase (JBM). The relative amounts of these mannose structures changed between the first and eighth day of diseases and also in comparison with the control serum (Figure 6). Since Man5 coelutes with FA2B structure, it was excluded from comparison in Figure 6B.
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Changes in the degree of branching
The degree of branching was measured after treating the glycan pool with a combination of ABS, SPG, and
-fucosidase from bovine kidney (BKF), which reduced the glycans into the core antenna structures (GlcNAc only attached to the trimannosyl chitobiose core mono-, bi-, tri-, and tetra-antennary structures). As shown in Figure 7A, the degree of branching in pancreatitis and sepsis was different from the control serum, and also changed during the course of the diseases.
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Other glycans
The control and sepsis samples also contained low levels of glycans with an N-acetyl-lactosamine extension as detected by the negative ion MS/MS. The spectra contained a very abundant F-type ion at m/z 789, confirming the antenna structure as Hex2HexNAc2. The high relative abundance of this ion is consistent with N-acetyl-lactosamine substitution on the 6-branch of the 6-antenna (Harvey 2005
). Both sepsis Day 1 and Day 8 had an additional N-acetyl-lactosamine-extended glycan with an additional fucose. The spectrum from Day 1 was weak but that from Day 8 showed 80% of the fucosylated structures had outer-arm fucose substitution in one of the antennae, and an F ion at m/z 935 (m/z 789 + 146) showed that at least some of this fucose was located in the N-acetyl-lactosamine-extended antenna. This compound was not detected in the early pancreatitis sample but was present on Day 8. |
Discussion |
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TopAbstractIntroductionResultsDiscussionMaterials and methodsFundingConflict of interest statementGlycan structuresReferences |
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Our results demonstrate that the changes of serum glycans occur very early in acute inflammation. The proportions of different glycans changed daily; some of them change continuously in the same direction, while others varied during the course of acute pancreatitis and sepsis. The most prominent changes that consistently followed disease progression were observed for tri- and tetrasialylated structures as well as for oligomannose structures. These structures were also found to be altered in the first day of both pancreatitis and sepsis (when compared to the control serum).
In sepsis, the proportion of the trisialylated triantennary A3G3S3 in total glycan pool constantly decreased, while in pancreatitis, the proportion of the sialyl Lewis X structure A3FG3S3 constantly increased. The acute-phase protein 1-acid glycoprotein, which is elevated early in the acute-phase response, has been recognized as a principal carrier of this Lewis antigen (Brinkman-van der Linden et al. 1998). Haptoglobin and 1-antichymotripsyn were also found to contribute to the elevation of sialyl-Lewis X, but to lesser extent. Earlier studies also reported the elevation of the expression of sialyl-Lewis X on 1-acid glycoprotein induced by inflammation, independent of the increase in the concentration of 1-acid glycoprotein (Higai et al. 2005). Similar observation was made in malignant diseases (Croce et al. 2005). It has been postulated that this increase might have beneficial effects by protecting the organism from overreaction that can occur during inflammation and which could be fatal (Bone 1996). Since the enzyme responsible for the addition of fucose to A3G3S3 is 1–3 fucosyltransferase, the levels of this enzyme are crucial. A study on 1-acid glycoprotein suggested that inflammatory cytokines regulate the expression of 1–3 fucosyltransferase VI responsible for 1–3 fucosylation in liver tissue (De Graaf et al. 1993; Higai et al. 2005), as well as the expression of 2–3 sialyltransferase required for sialyl-Lewis X formation (since only structures containing 2–3-linked Neu5Ac can be fucosylated). Work on the prognostic value of 1-acid glycoprotein glycosylation in septic shock (Brinkman-van der Linden et al. 1996) indicated that a modest elevation in biantennary glycans in combination with a strong increase in sialyl-Lewis X was associated with a higher mortality than a high transient increase in biantennary with gradually increasing sialyl-Lewis X expression. This clearly demonstrates that the manner of changes in glycan structures can be associated with the severity of a disease.
We found that the amounts of oligomannose structures constantly decreased with the progression of acute pancreatitis, while in sepsis they varied slightly throughout the days. However, in both diseases, these structures were markedly increased on Day 1 (compared to control) and then decreased on Day 8 (Man6 and Man9 fell to below the control level). These types of glycan structures can be found on the C3 component of complement (Hirani et al. 1986), which is also one of the positive acute-phase proteins. The complement pathway is derived from many small plasma proteins that form the biochemical cascade of the immune system. It is designed to destroy infectious microbes and damaged host material (Ritchie et al. 2002). In contrast to most of the components synthesized mainly in the liver that have complex biantennary structures, C3 contains only oligomannose types (Hase et al. 1985; Hirani et al. 1986), with predominantly Man8 and Man9 on the chain and Man6 on the ß chain.
Increases in biantennary glycans have been reported in patients with acute and chronic inflammatory conditions as well as in cancer (Higai et al. 2005). In our study, these compounds were also elevated, especially in the later stage of the acute response. In acute pancreatitis, biantennary glycans with bisecting GlcNAc were markedly elevated compared to the control. Tetraantennary structures were elevated in both diseases, although this elevation was more prominent in pancreatitis. Enzymes responsible for synthesising antennae on N-glycans are N-acetylglucosaminyl transferases (GnT). GnT III is the enzyme responsible for adding ß-GlcNAc to the 4-position of the mannose in the core of N-glycans forming a bisecting ß1-4 GlcNAc structure. GnT IV is responsible for forming triantennary structures by adding ß1-4 GlcNAc to the 3-antenna of the tri-mannosyl-chitobiose core, while tetraantennary glycans are produced by subsequent actions of this enzyme and GnT V that adds ß-GlcNAc to the 6-position of the mannose of the 6-antenna (Brockhausen et al. 1989). Increased activities of these enzymes have been reported in many human malignancies (Dennis and Laferte 1989; Yao et al. 1998; Takamatsu et al. 1999; Guo et al. 2001; Jin et al. 2004). Our results suggest an increase in the activity of these enzymes in the acute-phase response, especially in pancreatitis. An isoform of the triantennary glycans with a branched 6-antenna represents a significant proportion of the triantennary structures in both sepsis and pancreatitis, while in normal serum, the amount of this structure is almost negligible.
Comparison of tri- and tetra-antennary structures reveals that the ratio of 1–3-fucosylated forms to core fucosylated or nonfucosylated forms was increased in both pancreatitis and sepsis. This supports the previously presented hypothesis of increased 1–3 fucosyltransferase activity, and decreased activity of 1–6 fucosyltransferase in the acute-phase response. This alteration in core fucosylation is different from the findings in different human cancers (Ito et al. 2003; Block et al. 2005), as well as in pancreatic cancer (Barrabes et al. 2007), where the increase in core fucosylation was observed and even suggested as new diagnostic and prognostic marker. These changes in fucose levels can be a part of the regulatory processes during inflammation, since it was suggested that it participates in immune modulation (Bone 1996; Listinsky et al. 2001).
In general, our results show that the changes of serum glycans can be observed very early in acute inflammation and that the proportions of different structures change daily. Since glycan profiles in healthy serum are more or less constant, these changes apparently mirror the disease. The observed differences between sepsis and acute pancreatitis are probably due to the fact that, in these two conditions, the acute-phase response is triggered by different stimuli and is, thus, associated with different patterns of production of specific cytokines. This complexity is not surprising, knowing how complex and diverse the acute-phase response is, and how important roles glycans play in many different processes.
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Materials and methods |
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Serum samples
Serum samples were collected at the University Hospital Zagreb. Sera from a septic patient and a patient with acute pancreatitis were taken at the time of reporting to hospital, and then, three more times through the first eight days of hospitalization. The patients claimed to report to the hospital on the first day of feeling sick, so we assume it to be the first day of disease. The blood from a healthy individual, matched by sex and age, was drawn on one occasion only. The possibility of any inflammatory condition in the control subject was additionally excluded by measuring C-reactive protein (CRP was lower than 0. 5 mg/dL). The enrolled patients were individuals who fulfilled the clinical criteria of sepsis or acute pancreatitis and who had signed the informed consent to participate. This study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Boards of the University Hospital Center Zagreb and the University of Zagreb, Faculty of Pharmacy and Biochemistry.
Glycan release and labeling
The N-glycans from 10 µL of sera were analyzed, as described previously (Royle et al. submitted). Briefly, the proteins from sera were immobilized in a block of SDS-polyacrylamide gel and N-glycans were released by digestion with recombinant N-glycosidase F (PNGase F, Roche Diagnostics, Basel, Switzerland). After extraction, glycans were fluorescently labeled with 2-aminobenzamide (AB) (LudgerTag 2-AB labeling kit Ludger Ltd., Abingdon, U.K.).
NP-HPLC
The released glycans were then subjected to NP-HPLC on a TSK Amide-80 250 x 4.6 mm column (Anachem, Luton, Bedfordshire, U.K.) at 30°C with 50 mM formic acid adjusted to pH 4.4 with ammonia solution as solvent A and acetonitrile as solvent B. 180 and 120 min runs were on a 2695 Alliance separations module (Waters, Milford, MA). The HPLCs were equipped with a Waters temperature control module and a Waters 2475 fluorescence detector set with excitation and emission wavelengths of 330 and 420 nm. The system was calibrated by using an external standard of hydrolyzed and 2-AB-labeled glucose oligomers from which the retention times for the individual glycans were converted to glucose units (GU) (Royle et al. 2006). Glycans were analyzed on the basis of their elution positions and measured in GU and then compared to reference values in the "Glycobase" database (available at: http://glycobase.ucd.ie/cgi-bin/glycobase.cgi) for preliminary structure assignment (Royle et al. submitted).
WAX-HPLC
Glycans were separated according to the number of sialic acids by WAX HPLC. The analysis was performed by using a Vydac 301VHP575 7.5 x 50 mm column (Anachem Ltd., Luton, Bedfordshire, UK) (Royle et al. 2006). Compounds were retained on the column according to their charge density, the higher charged compounds being retained the longest. Separated fractions were collected and subjected to NP-HPLC.
Exoglycosidase digestions
Glycans, both from total glycan pool and WAX separated fractions, were sequenced by exoglycosidase digestions followed by NP-HPLC (Royle et al. 2006). The exoglycosidase digestions of 2-AB labeled glycans were carried out with the following enzymes obtained from Prozyme, San Leandro, CA: ABS, Arthrobacter ureafaciens sialidase (Glyko Sialidase A,) specific for 2–3,6,8 sialic acids; NAN1, Streptococcus. pneumoniae neuraminidase (Sialidase S) releases 2–3,8 linked sialic acid; BTG, Bovine testes ß-galactosidase specific for ß1–3,4 and 6 linked galactose; SPG, S. pneumoniae ß-galactosidase, specific for ß1–4-linked galactose; BKF, bovine kidney -fucosidase digests 1–2,6>>3,4-fucose; GUH, ß-N-acetyl-glucosaminidase digests N-acetylglucosamine but not the bisect; JBM, Jack Bean -mannosidase, AMF, Almond meal -fucosidase removes 1–3/4-fucose; XMF, Xanthomonus sp. 1–2-fucosidase (New England Biolabs, Hitchin, Herts, U.K.). The samples were incubated overnight at 37°C in 50 mM sodium acetate buffer, pH 5.5, except JBM digestion, which were in 100 mM sodium acetate, 2 mM Zn2+, pH 5.0.
Mass spectrometry
MALDI-TOF MS.
Desialylated glycan samples (1 µL of an aqueous solution) were cleaned with a Nafion 117 membrane (Börnsen et al. 1995) before analysis with 2,5-dihydroxybenzoic acid (DHB) on a Waters–Micromass (Manchester, U.K.) TofSpec 2E reflectron-TOF MS operated in reflectron mode with delayed extraction (Harvey 1993).
Nano-electrospray MS.
Nano-electrospray MS was performed with a Waters–Micromass quadrupole-time-of-flight (Q-TOF) Ultima Global instrument. Samples of non-2AB labeled glycans in 1:1 (v:v) methanol:water containing 0.5 mM ammonium phosphate were infused through Proxeon (Proxeon Biosystems, Odense, Denmark) nanospray capillaries as detailed in Harvey(2005).
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Funding |
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TopAbstractIntroductionResultsDiscussionMaterials and methodsFundingConflict of interest statementGlycan structuresReferences |
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Biotechnology and Biological Sciences Research Council and the Wellcome Trust; Oxford Glycobiology Institute; Croatian Ministry of Science, Education and Sport (#219–0061194-2023 and #006–0061194-1218); FP6-EuroPharm grant (European Commission).
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Conflict of interest statement |
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TopAbstractIntroductionResultsDiscussionMaterials and methodsFundingConflict of interest statementGlycan structuresReferences |
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None declared.
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Glycan structures |
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TopAbstractIntroductionResultsDiscussionMaterials and methodsFundingConflict of interest statementGlycan structuresReferences |
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Ax, number (x) of antenna (GlcNAc) on trimannosyl core; F, at the start of the abbreviation indicates a core fucose
1–6 linked to the inner GlcNAc; F(x), number (x) of fucose linked 1–3 to antenna GlcNAc; Gx, number (x) of ß1–4 linked galactose on antenna; G1[3] and G1[6] indicates that the galactose is on the antenna of the 1–3 or 1–6 mannose; Lac(x), number (x) of lactosamine (Galß1–4GlcNAc) extensions; Mx, number (x) of mannose on the core GlcNAc; Sx, number (x) of sialic acids linked to galactose; the numbers 3 or 6 in parentheses after S indicate whether the sialic acid is in an 2–3, 2–6 linkage.
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Footnotes |
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2Present address: Dublin-Oxford Glycobiology Laboratory, NIBRT, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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Abbreviations |
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2-AB, 2-aminobenzamide; ABS, sialidase from Arthrobacter ureafaciens; AMF, Almond meal
-fucosidase; BKF, -fucosidase from bovine kidney; BTG, ß-galactosidase from bovine testes; BTG, ß-galactosidase from bovine testes; CRP, C-reactive protein; DHB, dihydroxybenzoic acid; ESI, electrospray ionizatio; GnT , N-acetylglucosaminyl transferase; GU, glucose unit; GUH, ß-N-acetyl-hexosaminidase; HPLC, high-performance liquid chromatography; BM, Jack Bean -mannosidase; JBM, Jack Bean -mannosidase; MALDI, matrix-assisted laser desorption/ionization; MS, mass spectrometry; NAN1, neuraminidase from Streptococcus pneumoniae; NP, normal-phase; PNGase F, N-glycosidase F; QTOF, quadripole time-of-flight; SPG, ß-galactosidase from S. pneumoniae; WAX, weak anion exchange; XMF, -fucosidase from Xanthomonus sp |
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