Towards GAG glycomics: Analysis of highly sulfated heparins by MALDI-TOF mass spectrometry

Tissot, Bérangère; Gasiunas, Nijole; Powell, Andrew K.; Ahmed, Yassir A.; Zheng, Zhi; Haslam, Stuart M.; Morris, Howard R.; Turnbull, Jeremy E.; Gallagher, John T.; Dell, Anne

doi:10.1093/glycob/cwm072

Cited by 60 publications

(56 citation statements)

References 38 publications

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“…Two matrices have been investigated by Tissot et al (2007) for MALDI-TOF and MALDI-TOF/TOF analysis of GAGderived di-, tetra-, hexa-and deca-oligosaccharides carrying from 2 to 13 sulfate groups. The first, an ionic liquid, 1-ethylimidazolium (14) a-cyano-4-hydroxycinnamate (ImCHCA), produced very little loss of sulfate, a property attributed by the authors, to a high sodium content that stabilized the sulfates by salt formation.…”

Section: Analysis Of Carbohydrates and Glycoconjugatesmentioning

confidence: 99%

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

Harvey

2011

Mass Spectrometry Reviews

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This review is the fifth update of the original review, published in 1999, on the application of MALDI mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2008. The first section of the review covers fundamental studies, fragmentation of carbohydrate ions, use of derivatives and new software developments for analysis of carbohydrate spectra. Among newer areas of method development are glycan arrays, MALDI imaging and the use of ion mobility spectrometry. The second section of the review discusses applications of MALDI MS to the analysis of different types of carbohydrate. Specific compound classes that are covered include carbohydrate polymers from plants, N- and O-linked glycans from glycoproteins, biopharmaceuticals, glycated proteins, glycolipids, glycosides and various other natural products. There is a short section on the use of MALDI mass spectrometry for the study of enzymes involved in glycan processing and a section on the use of MALDI MS to monitor products of the chemical synthesis of carbohydrates with emphasis on carbohydrate-protein complexes and glycodendrimers. Corresponding analyses by electrospray ionization now appear to outnumber those performed by MALDI and the amount of literature makes a comprehensive review on this technique impractical. However, most of the work relating to sample preparation and glycan synthesis is equally relevant to electrospray and, consequently, those proposing analyses by electrospray should also find material in this review of interest.

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Section: Analysis Of Carbohydrates and Glycoconjugatesmentioning

confidence: 99%

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

Harvey

2011

Mass Spectrometry Reviews

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“…This correlation suggests that for diagnostic fragments, little or no desulfation occurred, and therefore the number of total sulfate groups can be determined for the analyzed oligosaccharides. The lack of desulfation observed is likely due to high content of sodium atoms acquired after the HPAEC-PAD separation step, which stabilizes the sulfate groups and partly prevent their elimination during the ionization process [22]. Although all the samples were analyzed with the three matrices and all the conditions, only the spectra providing useful and not superposing information were selected for clarity.…”

Section: Resultsmentioning

confidence: 99%

“…Recently [22], a MALDI MS strategy has been optimized for the analysis of high sulfated GAG-derived oligosaccharides, using a crystalline matrix nor-harmane and an ionic liquid 1-methylimidazolium ␣-cyano-4-hydroxycinnamate matrix. The maximum number of sulfate groups was found using the ionic liquid matrix, whereas MALDI-TOF/ TOF MS/MS experiments allowed the determination of the position of some sulfate groups.…”

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“…However, all these approaches have to be further developed until a reliable method of analysis of sulfated oligosaccharides may be used in routine determinations. In all cases, finding an ionization method soft enough to retain the labile sulfate groups, but at the same time able to produce sugar ring fragmentations required to obtain information about the precise position of them, remains the main problem [22,25].…”

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UV-MALDI-TOF mass spectrometry analysis of heparin oligosaccharides obtained by nitrous acid controlled degradation and high performance anion exchange chromatography

Bultel

Landoni

Grand

et al. 2010

J. Am. Soc. Mass Spectrom.

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Nitrous acid degradation of heparin followed by high-performance anion-exchange chromatography (HPAEC) separation and ultraviolet matrix assisted laser desorption/ionization time-of-flight (UV-MALDI-TOF) analysis led to the structural determination of six sulfated oligosaccharides. Three different matrices (␣-cyano-4-hydroxycinnamic acid (CHCA), norharmane, and dihydroxybenzoic acid (DHB)) have been used, and the complementary results obtained allowed in most cases to assign the position of sulfate groups. Based on the different cleavages produced on the purified oligosaccharides in source during the MS analysis by the use of the different matrices, this approach provides a new tool for structural analysis. (J Am Soc Mass Spectrom 2010, 21, 178 -190) © 2010 American Society for Mass Spectrometry G lycosaminoglycanes (GAGs), and more particularly heparan sulfates (HS), have been implicated in the regulation of a broad range of biological processes because of their specific interactions with a large number of proteins [1]. These interactions seem to depend on the number and position of sulfate groups in individual sugar moieties and on the way that sulfated glycosidic units are regrouped to form domains [2,3].The basic structure of heparin or heparan-like glycosaminoglycans is a disaccharide comprising an uronic acid residue linked 1¡4 to a glucosamine. It is repeated many times to form heterogeneous mixtures of chains with different lengths. Various modifications within the basic disaccharide unit, including two possible epimers of the uronic acid (l-iduronic and d-glucuronic), sulfation at the N, 3-O, 6-O position of the glucosamine and 2-O position of the uronic acid, generate a considerable amount of diversity.Among the existing strategies used in current glycobiology to study HS, genetic approaches have shown that targeting a particular sulfotransferase gene may perturb many sulfation patterns throughout the polysaccharide chain and therefore cannot be used to study the impact of a single structural feature [4]. On the other hand, a number of different chemical and biological approaches have led to the generation of size-defined heparin oligosaccharide libraries [5,6]. However their complete purification and the sequencing analytical and chemical methods used for their characterization are still extremely laborious, complex, and particularly limited by the small amounts of purified products available, compromising the efforts to relate a biological function to a specific sulfation sequence. The limited amounts of pure oligosaccharide fragments obtained also preclude structural characterization by the use of spectroscopic methods such as NMR.The availability of "soft ionization" techniques pointed to MS as an attractive and prominent analytical technique for structural elucidation. Characterization of heparin, HS, and other GAGs has been performed by fast atom bombardment (FAB) [7][8][9][10] and electrospray ionization (ESI) [11][12][13][14]. Different approaches using LC-ESI and tandem mass spectrometry (MS ...

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“…Nevertheless, CID has been used to differentiate 6-O-sulfo and 3-O-sulfo groups in Hp disaccharide units, due to differences in their multidimensional tandem mass spectrometry (MS n ) fragments (37). Metal cationization has also been used for the MS/MS analysis of carbohydrates (38 -42), and it has been found that increasing the charge state and metal-hydrogen exchange in these biomolecules increases the density of fragments and reduces SO 3 loss (17,25,43,44). Hp and HS GAGs have been characterized by their MS n with CID activation, for both multiply charged ions cationized by Ca 2ϩ (and Na ϩ to a lesser extent), ranging from a trisaccharide with four sulfo groups to a pentasaccharide with eight sulfo groups.…”

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Structurally Informative Tandem Mass Spectrometry of Highly Sulfated Natural and Chemoenzymatically Synthesized Heparin and Heparan Sulfate Glycosaminoglycans

Kailemia

et al. 2013

Molecular & Cellular Proteomics

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The highly sulfated glycosaminoglycan oligosaccharides derived from heparin and heparan sulfate have been a highly intractable class of molecules to analyze by tandem mass spectrometry. Under the many methods of ion activation, this class of molecules generally exhibits SO 3 loss as the most significant fragmentation pathway, interfering with the assignment of the location of sulfo groups in glycosaminoglycan chains. We report here a method that stabilizes sulfo groups and facilitates the complete structural analysis of densely sulfated (two or more sulfo groups per disaccharide repeat unit) heparin and heparan sulfate oligomers. This is achieved by complete removal of all ionizable protons, either by charging during electrospray ionization or by Na ؉ /H ؉ exchange. The addition of millimolar levels of NaOH to the sample solution facilitates the production of precursor ions that meet this criterion. This approach is found to work for a variety of heparin sulfate oligosaccharides derived from natural sources or produced by chemoenzymatic synthesis, with up to 12 saccharide subunits and up to 11 sulfo groups. Molecular & Cellular Proteomics 12: 10.1074/mcp.M112.026880, 979 -990, 2013. Heparin (Hp)1 and heparan sulfate (HS) are linear, polydisperse, and highly sulfated glycosaminoglycans (GAGs), with a repeating disaccharide building block composed of a 1-4-linked glucosamine and a uronic acid residue (1). The saccharide residues may have a variety of modifications, and these are usually heterogeneous due to the nontemplate nature of their biosynthesis (2). Glucosamine residues may be substituted with N-sulfo or N-acetyl and 3-and/or 6-O-sulfo groups. Uronic acid residues can be either glucuronic or iduronic acid and substituted with 2-O-sulfo groups (3, 4). These structural features are thought to control Hp and HS biological activity, e.g. their interactions with proteins, and so the structural characterization of GAGs is an important target for chemical analysis (1,5,6). A particularly well known example of a GAG-protein interaction is the role of Hp as an antithrombin III activator. A pentasaccharide unit with a very specific pattern of modification interacts with antithrombin III causing it to undergo a conformational change that increases the anticoagulation activity of antithrombin III by more than 3 orders of magnitude (7,8). Contamination of pharmaceutical Hp was a major issue recently, i.e. associated with over 70 fatalities worldwide (9 -12). This problem highlights the need for rapid, robust, and sensitive analytical methods for the analysis of heparin and for identifying contaminants of similar composition (11). Although nuclear magnetic resonance spectroscopy is often the method of choice for determining the structure of GAGs, such as Hp and HS, it requires substantial sample preparation to obtain pure samples, relatively large amounts of sample, and time-consuming interpretation.Mass spectrometry (MS) and tandem mass spectrometry (MS/MS) offer high sensitivity and specificity and are often used for t...

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Towards GAG glycomics: Analysis of highly sulfated heparins by MALDI-TOF mass spectrometry

Cited by 60 publications

References 38 publications

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

UV-MALDI-TOF mass spectrometry analysis of heparin oligosaccharides obtained by nitrous acid controlled degradation and high performance anion exchange chromatography

Structurally Informative Tandem Mass Spectrometry of Highly Sulfated Natural and Chemoenzymatically Synthesized Heparin and Heparan Sulfate Glycosaminoglycans

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