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Glycomics: an integrated systems approach to structure-function relationships of glycans

Nature Methods volume 2, pages 817–824 (2005)Cite this article

Abstract

In comparison with genomics and proteomics, the advancement of glycomics has faced unique challenges in the pursuit of developing analytical and biochemical tools and biological readouts to investigate glycan structure-function relationships. Glycans are more diverse in terms of chemical structure and information density than are DNA and proteins. This diversity arises from glycans' complex nontemplate-based biosynthesis, which involves several enzymes and isoforms of these enzymes. Consequently, glycans are expressed as an 'ensemble' of structures that mediate function. Moreover, unlike protein-protein interactions, which can be generally viewed as 'digital' in regulating function, glycan-protein interactions impinge on biological functions in a more 'analog' fashion that can in turn 'fine-tune' a biological response. This fine-tuning by glycans is achieved through the graded affinity, avidity and multivalency of their interactions. Given the importance of glycomics, this review focuses on areas of technologies and the importance of developing a bioinformatics platform to integrate the diverse datasets generated using the different technologies to allow a systems approach to glycan structure-function relationships.

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Figure 1: Chemical diversity of glycans.
Figure 2: Informatics approach to characterize glycans.
Figure 3: Glycan arrays to identify novel glycan specificities of proteins.

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References

  1. Lowe, J.B. & Marth, J.D. A genetic approach to mammalian glycan function. Annu. Rev. Biochem. 72, 643–691 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Varki, A. et al. Essentials of Glycobiology (Cold Spring Harber Laboratory Press, New York, 1999).

    Google Scholar 

  3. Taylor, M.E. & Drickamer, K. Introduction to glycobiology (Oxford University Press, Oxford and New York, 2003).

    Google Scholar 

  4. Raman, R., Sasisekharan, V. & Sasisekharan, R. Structural insights into biological roles of protein-glycosaminoglycan interactions. Chem. Biol. 12, 267–277 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Hwang, H.Y., Olson, S.K., Esko, J.D. & Horvitz, H.R. Caenorhabditis elegans early embryogenesis and vulval morphogenesis require chondroitin biosynthesis. Nature 423, 439–443 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Inatani, M., Irie, F., Plump, A.S., Tessier-Lavigne, M. & Yamaguchi, Y. Mammalian brain morphogenesis and midline axon guidance require heparan sulfate. Science 302, 1044–1046 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Lin, X. Functions of heparan sulfate proteoglycans in cell signaling during development. Development 131, 6009–6021 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Haltiwanger, R.S. & Lowe, J.B. Role of glycosylation in development. Annu. Rev. Biochem. 73, 491–537 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Cipollo, J.F., Awad, A.M., Costello, C.E. & Hirschberg, C.B. N-glycans of Caenorhabditis elegans are specific to developmental stages. J. Biol. Chem. 280, 26063–26072 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Sasisekharan, R., Shriver, Z., Venkataraman, G. & Narayanasami, U. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat. Rev. Cancer 2, 521–528 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Liu, D., Shriver, Z., Venkataraman, G., El Shabrawi, Y. & Sasisekharan, R. Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis. Proc. Natl. Acad. Sci. USA 99, 568–573 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fuster, M.M., Brown, J.R., Wang, L. & Esko, J.D. A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells. Cancer Res. 63, 2775–2781 (2003).

    CAS  PubMed  Google Scholar 

  13. Ishida, H. et al. A novel β1,3-N-acetylglucosaminyltransferase (β3Gn-T8), which synthesizes poly(N-acetyllactosamine), is dramatically upregulated in colon cancer. FEBS Lett. 579, 71–78 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Iwai, T. et al. Core 3 synthase is downregulated in colon carcinoma and profoundly suppresses the metastatic potential of carcinoma cells. Proc. Natl. Acad. Sci. USA 102, 4572–4577 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dube, D.H. & Bertozzi, C.R. Glycans in cancer and inflammation–potential for therapeutics and diagnostics. Nat. Rev. Drug Discov. 4, 477–488 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Casu, B., Guerrini, M. & Torri, G. Structural and conformational aspects of the anticoagulant and anti-thrombotic activity of heparin and dermatan sulfate. Curr. Pharm. Des. 10, 939–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Petitou, M. & van Boeckel, C.A. A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next? Angew. Chem. Int. Edn Engl. 43, 3118–3133 (2004).

    Article  CAS  Google Scholar 

  18. Shriver, Z., Liu, D. & Sasisekharan, R. Emerging views of heparan sulfate glycosaminoglycan structure/activity relationships modulating dynamic biological functions. Trends Cardiovasc. Med. 12, 71–77 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Kinjo, Y. et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434, 520–525 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Guo, Y. et al. Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR. Nat. Struct. Mol. Biol. 11, 591–598 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Crocker, P.R. Siglecs in innate immunity. Curr. Opin. Pharmacol. 5, 431–437 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Rudd, P.M., Wormald, M.R. & Dwek, R.A. Sugar-mediated ligand-receptor interactions in the immune system. Trends Biotechnol. 22, 524–530 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Rudd, P.M., Elliott, T., Cresswell, P., Wilson, I.A. & Dwek, R.A. Glycosylation and the immune system. Science 291, 2370–2376 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Collins, B.E. & Paulson, J.C. Cell surface biology mediated by low affinity multivalent protein-glycan interactions. Curr. Opin. Chem. Biol. 8, 617–625 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Crocker, P.R. Siglecs: sialic-acid-binding immunoglobulin-like lectins in cell-cell interactions and signalling. Curr. Opin. Struct. Biol. 12, 609–615 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Fry, E.E. et al. The structure and function of a foot-and-mouth disease virus-oligosaccharide receptor complex. EMBO J. 18, 543–554 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ganesh, V.K., Smith, S.A., Kotwal, G.J. & Murthy, K.H. Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation. Proc. Natl. Acad. Sci. USA 101, 8924–8929 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu, J. et al. Characterization of a heparan sulfate octasaccharide that binds to herpes simplex virus type 1 glycoprotein d. J. Biol. Chem. 277, 33456–33467 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Mahdavi, J. et al. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297, 573–578 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Miller, S.I., Ernst, R.K. & Bader, M.W. LPS, TLR4 and infectious disease diversity. Nat. Rev. Microbiol. 3, 36–46 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Shriver, Z., Raguram, S. & Sasisekharan, R. Glycomics: a pathway to a class of new and improved therapeutics. Nat. Rev. Drug Discov. 3, 863–873 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Sasisekharan, R. & Venkataraman, G. Heparin and heparan sulfate: biosynthesis, structure and function. Curr. Opin. Chem. Biol. 4, 626–631 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Sugahara, K. et al. Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr. Opin. Struct. Biol. 13, 612–620 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Blixt, O. et al. Chemoenzymatic synthesis of 2-azidoethyl-ganglio-oligosaccharides GD3, GT3, GM2, GD2, GT2, GM1, and GD1a. Carbohydr. Res. 340, 1963–1972 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Hanson, S., Best, M., Bryan, M.C. & Wong, C.H. Chemoenzymatic synthesis of oligosaccharides and glycoproteins. Trends Biochem. Sci. 29, 656–663 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Homeister, J.W., Daugherty, A. & Lowe, J.B. α(1,3)fucosyltransferases FucT-IV and FucT-VII control susceptibility to atherosclerosis in apolipoprotein E−/− mice. Arterioscler. Thromb. Vasc. Biol. 24, 1897–1903 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Smithson, G. et al. Fuc-TVII is required for T helper 1 and T cytotoxic 1 lymphocyte selectin ligand expression and recruitment in inflammation, and together with Fuc-TIV regulates naive T cell trafficking to lymph nodes. J. Exp. Med. 194, 601–614 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Martin, L.T., Marth, J.D., Varki, A. & Varki, N.M. Genetically altered mice with different sialyltransferase deficiencies show tissue-specific alterations in sialylation and sialic acid 9-O-acetylation. J. Biol. Chem. 277, 32930–32938 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Comelli, E.M., Amado, M., Head, S.R. & Paulson, J.C. Custom microarray for glycobiologists: considerations for glycosyltransferase gene expression profiling. Biochem. Soc. Symp. 69, 135–142 (2002).

    Article  CAS  Google Scholar 

  40. An, H.J., Peavy, T.R., Hedrick, J.L. & Lebrilla, C.B. Determination of N-glycosylation sites and site heterogeneity in glycoproteins. Anal. Chem. 75, 5628–5637 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Cipollo, J.F., Costello, C.E. & Hirschberg, C.B. The fine structure of Caenorhabditis elegans N-glycans. J. Biol. Chem. 277, 49143–49157 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Dell, A. & Morris, H.R. Glycoprotein structure determination by mass spectrometry. Science 291, 2351–2356 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Morelle, W., Page, A. & Michalski, J.C. Electrospray ionization ion trap mass spectrometry for structural characterization of oligosaccharides derivatized with 2-aminobenzamide. Rapid Commun. Mass Spectrom. 19, 1145–1158 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Morelle, W. et al. Fragmentation characteristics of permethylated oligosaccharides using a matrix-assisted laser desorption/ionization two-stage time-of-flight (TOF/TOF) tandem mass spectrometer. Rapid Commun. Mass Spectrom. 18, 2637–2649 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Kameyama, A. et al. Detection of oligosaccharides labeled with cyanine dyes using matrix-assisted laser desorption/ionization mass spectrometry. Anal. Chem. 76, 4537–4542 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Goldberg, D., Sutton-Smith, M., Paulson, J. & Dell, A. Automatic annotation of matrix-assisted laser desorption/ionization N-glycan spectra. Proteomics 5, 865–875 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Rudd, P.M. et al. A high-performance liquid chromatography based strategy for rapid, sensitive sequencing of N-linked oligosaccharide modifications to proteins in sodium dodecyl sulphate polyacrylamide electrophoresis gel bands. Proteomics 1, 285–294 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Royle, L. et al. An analytical and structural database provides a strategy for sequencing O-glycans from microgram quantities of glycoproteins. Anal. Biochem. 304, 70–90 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Ethier, M., Saba, J.A., Ens, W., Standing, K.G. & Perreault, H. Automated structural assignment of derivatized complex N-linked oligosaccharides from tandem mass spectra. Rapid Commun. Mass Spectrom. 16, 1743–1754 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Joshi, H.J. et al. Development of a mass fingerprinting tool for automated interpretation of oligosaccharide fragmentation data. Proteomics 4, 1650–1664 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Lohmann, K.K. & von der Lieth, C.W. GlycoFragment and GlycoSearchMS: web tools to support the interpretation of mass spectra of complex carbohydrates. Nucleic Acids Res. 32, W261–W266 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tang, H., Mechref, Y. & Novotny, M.V. Automated interpretation of MS/MS spectra of oligosaccharides. Bioinformatics 21 (Suppl. 1), i431–i439 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Park, Y. & Lebrilla, C.B. Application of Fourier transform ion cyclotron resonance mass spectrometry to oligosaccharides. Mass Spectrom. Rev. 24, 232–264 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Hakansson, K. et al. Electron capture dissociation and infrared multiphoton dissociation MS/MS of an N-glycosylated tryptic peptic to yield complementary sequence information. Anal. Chem. 73, 4530–4536 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. McFarland, M.A. et al. Structural characterization of the GM1 ganglioside by infrared multiphoton dissociation, electron capture dissociation, and electron detachment dissociation electrospray ionization FT-ICR MS/MS. J. Am. Soc. Mass Spectrom. 16, 752–762 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Froesch, M. et al. Coupling of fully automated chip electrospray to Fourier transform ion cyclotron resonance mass spectrometry for high-performance glycoscreening and sequencing. Rapid Commun. Mass Spectrom. 18, 3084–3092 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Zamfir, A. et al. Fully automated chip-based mass spectrometry for complex carbohydrate system analysis. Anal. Chem. 76, 2046–2054 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Guerrini, M., Bisio, A. & Torri, G. Combined quantitative 1H and 13C nuclear magnetic resonance spectroscopy for characterization of heparin preparations. Semin. Thromb. Hemost. 27, 473–482 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Manzi, A.E. et al. Exploring the glycan repertoire of genetically modified mice by isolation and profiling of the major glycan classes and nano-NMR analysis of glycan mixtures. Glycobiology 10, 669–689 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Lopez, M. et al. Microheterogeneity of the oligosaccharides carried by the recombinant bovine lactoferrin expressed in Mamestra brassicae cells. Glycobiology 7, 635–651 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Venkataraman, G., Shriver, Z., Raman, R. & Sasisekharan, R. Sequencing complex polysaccharides. Science 286, 537–542 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Guerrini, M. et al. A novel computational approach to integrate NMR spectroscopy and capillary electrophoresis for structure assignment of heparin and heparan sulfate oligosaccharides. Glycobiology 12, 713–719 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Sharon, N. & Lis, H. Lectins (Kluwer Academic Publishers, Boston, 2004).

    Google Scholar 

  64. Plante, O.J., Palmacci, E.R. & Seeberger, P.H. Automated solid-phase synthesis of oligosaccharides. Science 291, 1523–1527 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Hirabayashi, J. Lectin-based structural glycomics: glycoproteomics and glycan profiling. Glycoconj. J. 21, 35–40 (2004).

    Article  PubMed  Google Scholar 

  66. Feizi, T., Fazio, F., Chai, W. & Wong, C.H. Carbohydrate microarrays—a new set of technologies at the frontiers of glycomics. Curr. Opin. Struct. Biol. 13, 637–645 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Galanina, O.E., Mecklenburg, M., Nifantiev, N.E., Pazynina, G.V. & Bovin, N.V. GlycoChip: multiarray for the study of carbohydrate-binding proteins. Lab Chip 3, 260–265 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Blixt, O. et al. Printed covalent glycan array for ligand profiling of diverse glycan binding proteins. Proc. Natl. Acad. Sci. USA 101, 17033–17038 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. von der Lieth, C.W., Bohne-Lang, A., Lohmann, K.K. & Frank, M. Bioinformatics for glycomics: status, methods, requirements and perspectives. Brief. Bioinform. 5, 164–178 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Cooper, C.A., Harrison, M.J., Wilkins, M.R. & Packer, N.H. GlycoSuiteDB: a new curated relational database of glycoprotein glycan structures and their biological sources. Nucleic Acids Res. 29, 332–335 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kanehisa, M., Goto, S., Kawashima, S., Okuno, Y. & Hattori, M. The KEGG resource for deciphering the genome. Nucleic Acids Res. 32, D277–D280 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Aoki, K.F. et al. Application of a new probabilistic model for recognizing complex patterns in glycans. Bioinformatics 20 (Suppl. 1), I6–I14 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Bohne-Lang, A., Lang, E., Forster, T. & von der Lieth, C.W. LINUCS: linear notation for unique description of carbohydrate sequences. Carbohydr. Res. 336, 1–11 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Kikuchi, N. et al. The carbohydrate sequence markup language (CabosML): an XML description of carbohydrate structures. Bioinformatics 21, 1717–1718 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Lutteke, T., Frank, M. & von der Lieth, C.W. Data mining the protein data bank: automatic detection and assignment of carbohydrate structures. Carbohydr. Res. 339, 1015–1020 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Li, J. et al. The Molecule Pages database. Nature 420, 716–717 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the US National Institute of General Medical Sciences Glue Grant U54 GM62116. We thank the CFG members, the members of Bioinformatics Core (B) of CFG for the work described in this review and V. Sasisekharan for critical reading of the manuscript.

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  1. Ganesh Venkataraman

    Present address: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, Massachusetts, 02142, USA

Authors and Affiliations

  1. Biological Engineering Division, Center for Biomedical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA

    Rahul Raman, S Raguram, Ganesh Venkataraman & Ram Sasisekharan

  2. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    James C Paulson

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Correspondence to Ram Sasisekharan.

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G.V. is presently employed by Momenta Pharmaceuticals. R.S. is a consultant to Momenta Pharmaceuticals.

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Raman, R., Raguram, S., Venkataraman, G. et al. Glycomics: an integrated systems approach to structure-function relationships of glycans. Nat Methods 2, 817–824 (2005). https://doi.org/10.1038/nmeth807

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