Glycoscience research has been significantly impeded by the complex compositions of the glycans present in biological molecules and the lack of convenient tools suitable for studying the glycosylation process and its function. Polysaccharides and glycoconjugates are not encoded directly by genes; instead, their biosynthesis relies on the differential expression of carbohydrate enzymes, resulting in heterogeneous mixtures of glycoforms, each with a distinct physiological activity. Access to well-defined structures is required for functional study, and this has been provided by chemical and enzymatic synthesis and by the engineering of glycosylation pathways. This review covers general methods for preparing glycans commonly found in mammalian systems and applying them to the synthesis of therapeutically significant glycoconjugates (glycosaminoglycans, glycoproteins, glycolipids, glycosylphosphatidylinositol-anchored proteins) and the development of carbohydrate-based vaccines.


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Literature Cited

  1. Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P. 1.  et al. 2009. Essentials of Glycobiology Cold Spring Harbor, NY: Cold Spring Harb. Lab. Press
  2. Walt D, Aoki-Kinoshita KF, Bendiak B, Bertozzi CR, Boons G. 2.  et al. 2012. Transforming Glycoscience: A Roadmap for the Future Washington, DC: Natl. Acad. Press
  3. Hudak JE, Bertozzi CR. 3.  2014. Glycotherapy: New advances inspire a reemergence of glycans in medicine. Chem. Biol. 21:16–37 [Google Scholar]
  4. Wong C-H. 4.  2003. Carbohydrate-Based Drug Discovery, Vols. 1, 2 Weinheim, Ger: Wiley-VCH
  5. Bhaskar U, Sterner E, Hickey AM, Onishi A, Zhang F. 5.  et al. 2012. Engineering of routes to heparin and related polysaccharides. Appl. Microbiol. Biotechnol. 93:1–16 [Google Scholar]
  6. Verez-Bencomo V, Fernandez-Santana V, Hardy E, Toledo ME, Rodriguez MC. 6.  et al. 2004. A synthetic conjugate polysaccharide vaccine against Haemophilus influenzae type b. Science 305:522–25 [Google Scholar]
  7. Kiessling LL, Splain RA. 7.  2010. Chemical approaches to glycobiology. Annu. Rev. Biochem. 79:619–53 [Google Scholar]
  8. Hsu CH, Hung SC, Wu CY, Wong CH. 8.  2011. Toward automated oligosaccharide synthesis. Angew. Chem. Int. Ed. Engl. 50:11872–923 [Google Scholar]
  9. Boltje TJ, Buskas T, Boons G-J. 9.  2009. Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research. Nat. Chem. 1:611–22 [Google Scholar]
  10. Galan MC, Benito-Alifonso D, Watt GM. 10.  2011. Carbohydrate chemistry in drug discovery. Org. Biomol. Chem. 9:3598–610 [Google Scholar]
  11. Wang L-X, Davis B. 11.  2013. Realizing the promise of chemical glycobiology. Chem. Sci. 4:3381–94 [Google Scholar]
  12. Fisher E. 11a.  1902. Nobel lecture: syntheses in the purine and sugar group. Nobel Media AB, 2014. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1902/fischer-lecture.pdf
  13. Zhu X, Schmidt RR. 12.  2009. New principles for glycoside-bond formation. Angew. Chem. Int. Ed. Engl. 48:1900–34 [Google Scholar]
  14. Demchenko AV. 13.  2008. Handbook of Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance Weinheim, Ger: Wiley-VCH
  15. Seeberger PH. 14.  2015. The logic of automated glycan assembly. Acc. Chem. Res. 48:1450–63 [Google Scholar]
  16. Yasomanee JP, Demchenko AV. 15.  2013. From stereocontrolled glycosylation to expeditious oligosaccharide synthesis. Trends Glycosci. Glycotechnol. 25:13–42 [Google Scholar]
  17. Ali IAI, El Ashry ESH, Schmidt RR. 16.  2003. Protection of hydroxy groups with diphenylmethyl and 9-fluorenyl trichloroacetimidates—effect on anomeric stereocontrol. Eur. J. Org. Chem. 2003:4121–31 [Google Scholar]
  18. Kim JH, Yang H, Park J, Boons GJ. 17.  2005. A general strategy for stereoselective glycosylations. J. Am. Chem. Soc. 127:12090–97 [Google Scholar]
  19. Crich D. 18.  2011. Methodology development and physical organic chemistry: a powerful combination for the advancement of glycochemistry. J. Org. Chem. 76:9193–209 [Google Scholar]
  20. Imamura A, Ando H, Korogi S, Tanabe G, Muraoka O. 19.  et al. 2003. Di-tert-butylsilylene (DTBS) group-directed α-selective galactosylation unaffected by C-2 participating functionalities. Tetrahedron Lett. 44:6725–28 [Google Scholar]
  21. Benakli K, Zha C, Kerns RJ. 20.  2001. Oxazolidinone protected 2-amino-2-deoxy-d-glucose derivatives as versatile intermediates in stereoselective oligosaccharide synthesis and the formation of α-linked glycosides. J. Am. Chem. Soc. 123:9461–62 [Google Scholar]
  22. Manabe S, Ishii K, Ito Y. 21.  2006. N-benzyl-2,3-oxazolidinone as a glycosyl donor for selective α-glycosylation and one-pot oligosaccharide synthesis involving 1,2-cis-glycosylation. J. Am. Chem. Soc. 128:10666–67 [Google Scholar]
  23. Olsson JD, Eriksson L, Lahmann M, Oscarson S. 22.  2008. Investigations of glycosylation reactions with 2-N-acetyl-2N,3O-oxazolidinone-protected glucosamine donors. J. Org. Chem. 73:7181–88 [Google Scholar]
  24. Hsu CH, Chu KC, Lin YS, Han JL, Peng YS. 23.  et al. 2010. Highly α-selective sialyl phosphate donors for efficient preparation of natural sialosides. Chemistry 16:1754–60 [Google Scholar]
  25. Wang CH, Li ST, Lin TL, Cheng YY, Sun TH. 24.  et al. 2013. Synthesis of Neisseria meningitidis serogroup W135 capsular oligosaccharides for immunogenicity comparison and vaccine development. Angew. Chem. Int. Ed. Engl. 52:9157–61 [Google Scholar]
  26. Chu KC, Ren CT, Lu CP, Hsu CH, Sun TH. 25.  et al. 2011. Efficient and stereoselective synthesis of α(2 → 9) oligosialic acids: from monomers to dodecamers. Angew. Chem. Int. Ed. Engl. 50:9391–95 [Google Scholar]
  27. Mulani SK, Hung W-C, Ingle AB, Shiau K-S, Mong K-KT. 26.  2014. Modulating glycosylation with exogenous nucleophiles: an overview. Org. Biomol. Chem. 12:1184–97 [Google Scholar]
  28. Raghavan S, Kahne D. 27.  1993. A one step synthesis of the ciclamycin trisaccharide. J. Am. Chem. Soc. 115:1580–81 [Google Scholar]
  29. Mootoo DR, Konradsson P, Udodong U, Fraser-Reid B. 28.  1988. Armed and disarmed n-pentenyl glycosides in saccharide couplings leading to oligosaccharides. J. Am. Chem. Soc. 110:5583–84 [Google Scholar]
  30. Jensen HH, Pedersen CM, Bols M. 29.  2007. Going to extremes: “super” armed glycosyl donors in glycosylation chemistry. Chemistry 13:7576–82 [Google Scholar]
  31. Hsu Y, Lu XA, Zulueta MM, Tsai CM, Lin KI. 30.  et al. 2012. Acyl and silyl group effects in reactivity-based one-pot glycosylation: synthesis of embryonic stem cell surface carbohydrates Lc4 and IV2Fuc-Lc4. J. Am. Chem. Soc. 134:4549–52 [Google Scholar]
  32. Douglas NL, Ley SV, Lucking U, Warriner SL. 31.  1998. Tuning glycoside reactivity: new tool for efficient oligosaccharide synthesis. J. Chem. Soc. Perkin Trans. 1 1998:51–66 [Google Scholar]
  33. Huang X, Huang L, Wang H, Ye XS. 32.  2004. Iterative one-pot synthesis of oligosaccharides. Angew. Chem. Int. Ed. Engl. 43:5221–24 [Google Scholar]
  34. Yamada H, Harada T, Miyazaki H, Takahashi T. 33.  1994. One-pot sequential glycosylation: a new method for the synthesis of oligosaccharides. Tetrahedron Lett. 35:3979–82 [Google Scholar]
  35. Wang C-C, Lee J-C, Luo S-Y, Kulkarni SS, Huang Y-W. 34.  et al. 2007. Regioselective one-pot protection of carbohydrates. Nature 446:896–99 [Google Scholar]
  36. Francais A, Urban D, Beau JM. 35.  2007. Tandem catalysis for a one-pot regioselective protection of carbohydrates: the example of glucose. Angew. Chem. Int. Ed. Engl. 46:8662–65 [Google Scholar]
  37. Zhang Z, Ollmann IR, Ye X-S, Wischnat R, Baasov T, Wong C-H. 36.  1999. Programmable one-pot oligosaccharide synthesis. J. Am. Chem. Soc. 121:734–53 [Google Scholar]
  38. Burkhart F, Zhang Z, Wacowich-Sgarbi S, Wong CH. 37.  2001. Synthesis of the Globo H hexasaccharide using the programmable reactivity-based one-pot strategy. Angew. Chem. Int. Ed. Engl. 40:1274–77 [Google Scholar]
  39. Plante OJ, Palmacci ER, Seeberger PH. 38.  2001. Automated solid-phase synthesis of oligosaccharides. Science 291:1523–27 [Google Scholar]
  40. Werz DB, Castagner B, Seeberger PH. 39.  2007. Automated synthesis of the tumor-associated carbohydrate antigens Gb-3 and Globo-H: incorporation of α-galactosidic linkages. J. Am. Chem. Soc. 129:2770–71 [Google Scholar]
  41. Geyer K, Gustafsson T, Seeberger PH. 40.  2009. Developing continuous-flow microreactors as tools for synthetic chemists. Synlett 2009:2382–91 [Google Scholar]
  42. Jaipuri FA, Pohl NL. 41.  2008. Toward solution-phase automated iterative synthesis: fluorous-tag assisted solution-phase synthesis of linear and branched mannose oligomers. Org. Biomol. Chem. 6:2686–91 [Google Scholar]
  43. Zhang F, Zhang W, Zhang Y, Curran DP, Liu G. 42.  2009. Synthesis and applications of a light-fluorous glycosyl donor. J. Org. Chem. 74:2594–97 [Google Scholar]
  44. Nokami T, Hayashi R, Saigusa Y, Shimizu A, Liu CY. 43.  et al. 2013. Automated solution-phase synthesis of oligosaccharides via iterative electrochemical assembly of thioglycosides. Org. Lett. 15:4520–23 [Google Scholar]
  45. Yamada K, Nishimura S-I. 44.  1995. An efficient synthesis of sialoglycoconjugates on a peptidase-sensitive polymer support. Tetrahedron Lett. 36:9493–96 [Google Scholar]
  46. Ono Y, Kitajima M, Daikoku S, Shiroya T, Nishihara S. 45.  et al. 2008. Sequential enzymatic glycosyltransfer reactions on a microfluidic device: synthesis of a glycosaminoglycan linkage region tetrasaccharide. Lab Chip 8:2168–73 [Google Scholar]
  47. Martin JG, Gupta M, Xu Y, Akella S, Liu J. 46.  et al. 2009. Toward an artificial golgi: redesigning the biological activities of heparan sulfate on a digital microfluidic chip. J. Am. Chem. Soc. 131:11041–48 [Google Scholar]
  48. Schmaltz RM, Hanson SR, Wong CH. 47.  2011. Enzymes in the synthesis of glycoconjugates. Chem. Rev. 111:4259–307 [Google Scholar]
  49. Koeller KM, Wong CH. 48.  2000. Synthesis of complex carbohydrates and glycoconjugates: enzyme-based and programmable one-pot strategies. Chem. Rev. 100:4465–93 [Google Scholar]
  50. Wong C-H, Haynie S, Whitesides G. 49.  1982. Enzyme-catalyzed synthesis of N-acetyllactosamine with in situ regeneration of uridine 5′-diphosphate glucose and uridine 5′-diphosphate galactose. J. Org. Chem. 47:5416–18 [Google Scholar]
  51. Cai L. 50.  2012. Recent progress in enzymatic synthesis of sugar nucleotides. J. Carbohydr. Chem. 31:535–52 [Google Scholar]
  52. Ichikawa Y, Lin YC, Dumas DP, Shen GJ, Garcia-Junceda E. 51.  et al. 1992. Chemical-enzymatic synthesis and conformational analysis of sialyl Lewis x and derivatives. J. Am. Chem. Soc. 114:9283–98 [Google Scholar]
  53. Burkart MD, Izumi M, Wong C-H. 52.  1999. Enzymatic regeneration of 3′-phosphoadenosine-5′-phosphosulfate using aryl sulfotransferase for the preparative enzymatic synthesis of sulfated carbohydrates. Angew. Chem. Int. Ed. Engl. 38:2747–50 [Google Scholar]
  54. Yu H, Lau K, Thon V, Autran CA, Jantscher-Krenn E. 53.  et al. 2014. Synthetic disialyl hexasaccharides protect neonatal rats from necrotizing enterocolitis. Angew. Chem. Int. Ed. Engl. 53:6687–91 [Google Scholar]
  55. Zhou X, Chandarajoti K, Pham TQ, Liu R, Liu J. 54.  2011. Expression of heparan sulfate sulfotransferases in Kluyveromyces lactis and preparation of 3′-phosphoadenosine-5′-phosphosulfate. Glycobiology 21:771–80 [Google Scholar]
  56. De Luca C, Lansing M, Martini M, Crescenzi F, Shen G-J. 55.  et al. 1995. Enzymatic synthesis of hyaluronic acid with regeneration of sugar nucleotides. J. Am. Chem. Soc. 117:5869–70 [Google Scholar]
  57. Tsai TI, Lee HY, Chang SH, Wang CH, Tu YC. 56.  et al. 2013. Effective sugar nucleotide regeneration for the large-scale enzymatic synthesis of Globo H and SSEA4. J. Am. Chem. Soc. 135:14831–39 [Google Scholar]
  58. Shivatare SS, Chang SH, Tsai TI, Ren CT, Chuang HY. 57.  et al. 2013. Efficient convergent synthesis of bi-, tri-, and tetra-antennary complex type N-glycans and their HIV-1 antigenicity. J. Am. Chem. Soc. 135:15382–91 [Google Scholar]
  59. Nycholat CM, Peng W, McBride R, Antonopoulos A, de Vries RP. 58.  et al. 2013. Synthesis of biologically active N- and O-linked glycans with multisialylated poly-N-acetyllactosamine extensions using P. damsela α-6-sialyltransferase. J. Am. Chem. Soc. 135:18280–83 [Google Scholar]
  60. Huang W, Li C, Li B, Umekawa M, Yamamoto K. 59.  et al. 2009. Glycosynthases enable a highly efficient chemoenzymatic synthesis of N-glycoproteins carrying intact natural N-glycans. J. Am. Chem. Soc. 131:2214–23 [Google Scholar]
  61. Mackenzie LF, Wang Q, Warren RAJ, Withers SG. 60.  1998. Glycosynthases: mutant glycosidases for oligosaccharide synthesis. J. Am. Chem. Soc. 120:5583–84 [Google Scholar]
  62. Nakai H, Kitaoka M, Svensson B, Ohtsubo K. 61.  2013. Recent development of phosphorylases possessing large potential for oligosaccharide synthesis. Curr. Opin. Chem. Biol. 17:301–9 [Google Scholar]
  63. O'Neill EC, Field RA. 62.  2015. Enzymatic synthesis using glycoside phosphorylases. Carbohydr. Res. 403:23–37 [Google Scholar]
  64. Peterson S, Frick A, Liu J. 63.  2009. Design of biologically active heparan sulfate and heparin using an enzyme-based approach. Nat. Prod. Rep. 26:610–27 [Google Scholar]
  65. Chappell EP, Liu J. 64.  2013. Use of biosynthetic enzymes in heparin and heparan sulfate synthesis. Bioorg. Med. Chem. 21:4786–92 [Google Scholar]
  66. Li JP. 65.  2010. Glucuronyl C5-epimerase an enzyme converting glucuronic acid to iduronic acid in heparan sulfate/heparin biosynthesis. Prog. Mol. Biol. Transl. Sci. 93:59–78 [Google Scholar]
  67. Chapman E, Hanson SR. 66.  2012. Sulfotransferases and sulfatases: sulfate modification of carbohydrates. Carbohydrate-Modifying Biocatalysts P Grunwald 329–96 Singapore: Pan Stanford [Google Scholar]
  68. Xu D, Esko JD. 67.  2014. Demystifying heparan sulfate–protein interactions. Annu. Rev. Biochem. 83:129–57 [Google Scholar]
  69. Pulsipher A, Griffin ME, Stone SE, Brown JM, Hsieh-Wilson LC. 68.  2014. Directing neuronal signaling through cell-surface glycan engineering. J. Am. Chem. Soc. 136:6794–97 [Google Scholar]
  70. Pulsipher A, Griffin ME, Stone SE, Hsieh-Wilson LC. 69.  2015. Long-lived engineering of glycans to direct stem cell fate. Angew. Chem. Int. Ed. Engl. 54:1466–70 [Google Scholar]
  71. Huang ML, Smith RA, Trieger GW, Godula K. 70.  2014. Glycocalyx remodeling with proteoglycan mimetics promotes neural specification in embryonic stem cells. J. Am. Chem. Soc. 136:10565–68 [Google Scholar]
  72. DeAngelis PL, Liu J, Linhardt RJ. 71.  2013. Chemoenzymatic synthesis of glycosaminoglycans: re-creating, re-modeling and re-designing nature's longest or most complex carbohydrate chains. Glycobiology 23:764–77 [Google Scholar]
  73. DeAngelis PL. 72.  2012. Glycosaminoglycan polysaccharide biosynthesis and production: today and tomorrow. Appl. Microbiol. Biotechnol. 94:295–305 [Google Scholar]
  74. Fujikawa S, Ohmae M, Kobayashi S. 73.  2005. Enzymatic synthesis of chondroitin 4-sulfate with well-defined structure. Biomacromology 6:2935–42 [Google Scholar]
  75. Xu Y, Masuko S, Takieddin M, Xu H, Liu R. 74.  et al. 2011. Chemoenzymatic synthesis of homogeneous ultralow molecular weight heparins. Science 334:498–501 [Google Scholar]
  76. Sheng J, Xu Y, Dulaney SB, Huang X, Liu J. 75.  2012. Uncovering biphasic catalytic mode of C5-epimerase in heparan sulfate biosynthesis. J. Biol. Chem. 287:20996–1002 [Google Scholar]
  77. Dulaney SB, Huang X. 76.  2012. Strategies in synthesis of heparin/heparan sulfate oligosaccharides: 2000–present. Adv. Carbohydr. Chem. Biochem. 67:95–136 [Google Scholar]
  78. Endo M, Kakizaki I. 77.  2012. Synthesis of neoproteoglycans using the transglycosylation reaction as a reverse reaction of endo-glycosidases. Proc. Jpn. Acad. B 88:327–44 [Google Scholar]
  79. Yamaguchi M, Takagaki K, Kojima K, Hayashi N, Chen F. 78.  et al. 2010. Novel proteoglycan glycotechnology: chemoenzymatic synthesis of chondroitin sulfate-containing molecules and its application. Glycoconj. J. 27:189–98 [Google Scholar]
  80. Oh YI, Sheng GJ, Chang S-K, Hsieh-Wilson LC. 79.  2013. Tailored glycopolymers as anticoagulant heparin mimetics. Angew. Chem. Int. Ed. Engl. 52:11796–99 [Google Scholar]
  81. Moremen KW, Tiemeyer M, Nairn AV. 80.  2012. Vertebrate protein glycosylation: diversity, synthesis and function. Nat. Rev. Mol. Cell Biol. 13:448–62 [Google Scholar]
  82. Sola RJ, Griebenow K. 81.  2009. Effects of glycosylation on the stability of protein pharmaceuticals. J. Pharm. Sci. 98:1223–45 [Google Scholar]
  83. Datta P, Linhardt RJ, Sharfstein ST. 82.  2013. An 'omics approach towards CHO cell engineering. Biotechnol. Bioeng. 110:1255–71 [Google Scholar]
  84. Freeze HH. 83.  2013. Understanding human glycosylation disorders: Biochemistry leads the charge. J. Biol. Chem. 288:6936–45 [Google Scholar]
  85. Hebert DN, Lamriben L, Powers ET, Kelly JW. 84.  2014. The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis. Nat. Chem. Biol. 10:902–10 [Google Scholar]
  86. Wang L-X, Amin M. 85.  2014. Chemical and chemoenzymatic synthesis of glycoproteins for deciphering functions. Chem. Biol. 21:51–66 [Google Scholar]
  87. Wang LX, Lomino JV. 86.  2012. Emerging technologies for making glycan-defined glycoproteins. ACS Chem. Biol. 7:110–22 [Google Scholar]
  88. Marino K, Bones J, Kattla JJ, Rudd PM. 87.  2010. A systematic approach to protein glycosylation analysis: a path through the maze. Nat. Chem. Biol. 6:713–23 [Google Scholar]
  89. Helenius A, Aebi M. 88.  2001. Intracellular functions of N-linked glycans. Science 291:2364–69 [Google Scholar]
  90. Spiro RG. 89.  2002. Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds. Glycobiology 12:43R–56R [Google Scholar]
  91. Hossler P, Khattak SF, Li ZJ. 90.  2009. Optimal and consistent protein glycosylation in mammalian cell culture. Glycobiology 19:936–49 [Google Scholar]
  92. Yang Z, Wang S, Halim A, Schulz MA, Frodin M. 91.  et al. 2015. Engineered CHO cells for production of diverse, homogeneous glycoproteins. Nat. Biotechnol. 33:842–44 [Google Scholar]
  93. Varki A, Gagneux P. 92.  2012. Multifarious roles of sialic acids in immunity. Ann. N.Y. Acad. Sci. 1253:16–36 [Google Scholar]
  94. Rillahan CD, Antonopoulos A, Lefort CT, Sonon R, Azadi P. 93.  et al. 2012. Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome. Nat. Chem. Biol. 8:661–68 [Google Scholar]
  95. Okeley NM, Alley SC, Anderson ME, Boursalian TE, Burke PJ. 94.  et al. 2013. Development of orally active inhibitors of protein and cellular fucosylation. PNAS 110:5404–9 [Google Scholar]
  96. De Pourcq K, De Schutter K, Callewaert N. 95.  2010. Engineering of glycosylation in yeast and other fungi: current state and perspectives. Appl. Microbiol. Biotechnol. 87:1617–31 [Google Scholar]
  97. Merritt JH, Ollis AA, Fisher AC, DeLisa MP. 96.  2013. Glycans-by-design: engineering bacteria for the biosynthesis of complex glycans and glycoconjugates. Biotechnol. Bioeng. 110:1550–64 [Google Scholar]
  98. Vogl T, Hartner FS, Glieder A. 97.  2013. New opportunities by synthetic biology for biopharmaceutical production in Pichia pastoris. Curr. Opin. Biotechnol. 24:1094–101 [Google Scholar]
  99. Vidarsson G, Dekkers G, Rispens T. 98.  2014. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5:520 [Google Scholar]
  100. Shields RL, Lai J, Keck R, O'Connell LY, Hong K. 99.  et al. 2002. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcγ RIII and antibody-dependent cellular toxicity. J. Biol. Chem. 277:26733–40 [Google Scholar]
  101. Ferrara C, Grau S, Jager C, Sondermann P, Brunker P. 100.  et al. 2011. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. PNAS 108:12669–74 [Google Scholar]
  102. Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y. 101.  et al. 2003. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. 278:3466–73 [Google Scholar]
  103. Lin C-W, Tsai M-H, Li S-T, Tsai T-I, Chu K-C. 102.  et al. 2015. Glycan structure on immunoglobulin G for enhancement of effector functions. PNAS 112:10611–16 [Google Scholar]
  104. Anthony RM, Nimmerjahn F, Ashline DJ, Reinhold VN, Paulson JC, Ravetch JV. 103.  2008. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320:373–76 [Google Scholar]
  105. Kaneko Y, Nimmerjahn F, Ravetch JV. 104.  2006. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–73 [Google Scholar]
  106. Egrie JC, Browne JK. 105.  2001. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br. J. Cancer 84:Suppl. 13–10 [Google Scholar]
  107. Erbayraktar S, Grasso G, Sfacteria A, Xie QW, Coleman T. 106.  et al. 2003. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. PNAS 100:6741–46 [Google Scholar]
  108. Serna S, Yan S, Martin-Lomas M, Wilson IB, Reichardt NC. 107.  2011. Fucosyltransferases as synthetic tools: glycan array based substrate selection and core fucosylation of synthetic N-glycans. J. Am. Chem. Soc. 133:16495–502 [Google Scholar]
  109. Wang Z, Chinoy ZS, Ambre SG, Peng W, McBride R. 108.  et al. 2013. A general strategy for the chemoenzymatic synthesis of asymmetrically branched N-glycans. Science 341:379–83 [Google Scholar]
  110. Li L, Liu Y, Ma C, Qu J, Calderon AD. 109.  et al. 2015. Efficient chemoenzymatic synthesis of an N-glycan isomer library. Chem. Sci. 6:5652–61 [Google Scholar]
  111. Shivatare SS, Chang S-H, Tsai T-I, Tseng SY, Shivatare VS. 110.  et al. 2016. Modular synthesis of N-glycans and arrays for the hetero-ligand binding analysis of HIV antibodies. Nat. Chem. 8338–46
  112. Koizumi A, Matsuo I, Takatani M, Seko A, Hachisu M. 111.  et al. 2013. Top-down chemoenzymatic approach to a high-mannose-type glycan library: synthesis of a common precursor and its enzymatic trimming. Angew. Chem. Int. Ed. Engl. 52:7426–31 [Google Scholar]
  113. Witte K, Sears P, Martin R, Wong C-H. 112.  1997. Enzymatic glycoprotein synthesis: preparation of ribonuclease glycoforms via enzymatic glycopeptide condensation and glycosylation. J. Am. Chem. Soc. 119:2114–18 [Google Scholar]
  114. Takegawa K, Tabuchi M, Yamaguchi S, Kondo A, Kato I, Iwahara S. 113.  1995. Synthesis of neoglycoproteins using oligosaccharide-transfer activity with endo-β-N-acetylglucosaminidase. J. Biol. Chem. 270:3094–99 [Google Scholar]
  115. Goodfellow JJ, Baruah K, Yamamoto K, Bonomelli C, Krishna B. 114.  et al. 2012. An endoglycosidase with alternative glycan specificity allows broadened glycoprotein remodelling. J. Am. Chem. Soc. 134:8030–33 [Google Scholar]
  116. Mohorko E, Owen RL, Malojcic G, Brozzo MS, Aebi M, Glockshuber R. 115.  2014. Structural basis of substrate specificity of human oligosaccharyl transferase subunit N33/Tusc3 and its role in regulating protein N-glycosylation. Structure 22:590–601 [Google Scholar]
  117. Lizak C, Gerber S, Numao S, Aebi M, Locher KP. 116.  2011. X-ray structure of a bacterial oligosaccharyltransferase. Nature 474:350–55 [Google Scholar]
  118. Valderrama-Rincon JD, Fisher AC, Merritt JH, Fan Y-Y, Reading CA. 117.  et al. 2012. An engineered eukaryotic protein glycosylation pathway in Escherichia coli. Nat. Chem. Biol. 8:434–36 [Google Scholar]
  119. Lomino JV, Naegeli A, Orwenyo J, Amin MN, Aebi M, Wang LX. 118.  2013. A two-step enzymatic glycosylation of polypeptides with complex N-glycans. Bioorg. Med. Chem. 21:2262–70 [Google Scholar]
  120. Chalker JM, Bernardes GJ, Davis BG. 119.  2011. A “tag-and-modify” approach to site-selective protein modification. Acc. Chem. Res. 44:730–41 [Google Scholar]
  121. Paszek MJ, DuFort CC, Rossier O, Bainer R, Mouw JK. 120.  et al. 2014. The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 511:319–25 [Google Scholar]
  122. Hudak JE, Canham SM, Bertozzi CR. 121.  2014. Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion. Nat. Chem. Biol. 10:69–75 [Google Scholar]
  123. Unverzagt C, Kajihara Y. 122.  2013. Chemical assembly of N-glycoproteins: a refined toolbox to address a ubiquitous posttranslational modification. Chem. Soc. Rev. 42:4408–20 [Google Scholar]
  124. Payne RJ, Wong CH. 123.  2010. Advances in chemical ligation strategies for the synthesis of glycopeptides and glycoproteins. Chem. Commun. 46:21–43 [Google Scholar]
  125. Okamoto R, Souma S, Kajihara Y. 124.  2009. Efficient substitution reaction from cysteine to the serine residue of glycosylated polypeptide: repetitive peptide segment ligation strategy and the synthesis of glycosylated tetracontapeptide having acid labile sialyl-TN antigens. J. Org. Chem. 74:2494–501 [Google Scholar]
  126. Brik A, Yang YY, Ficht S, Wong CH. 125.  2006. Sugar-assisted glycopeptide ligation. J. Am. Chem. Soc. 128:5626–27 [Google Scholar]
  127. Yang YY, Ficht S, Brik A, Wong CH. 126.  2007. Sugar-assisted ligation in glycoprotein synthesis. J. Am. Chem. Soc. 129:7690–701 [Google Scholar]
  128. Payne RJ, Ficht S, Tang S, Brik A, Yang YY. 127.  et al. 2007. Extended sugar-assisted glycopeptide ligations: development, scope, and applications. J. Am. Chem. Soc. 129:13527–36 [Google Scholar]
  129. Ficht S, Payne RJ, Brik A, Wong CH. 128.  2007. Second-generation sugar-assisted ligation: a method for the synthesis of cysteine-containing glycopeptides. Angew. Chem. Int. Ed. Engl. 46:5975–79 [Google Scholar]
  130. Wang P, Dong S, Shieh J-H, Peguero E, Hendrickson R. 129.  et al. 2013. Erythropoietin derived by chemical synthesis. Science 342:1357–60 [Google Scholar]
  131. Wilson R, Dong S, Wang P, Danishefsky S. 130.  2013. The winding pathway to erythropoietin along the chemistry–biology frontier: a success at last. Angew. Chem. Int. Ed. Engl. 52:7646–65 [Google Scholar]
  132. O'Conner SE, Imperiali B. 131.  1998. A molecular basis for glycosylation-induced conformational switching. Chem. Biol. 5:427–37 [Google Scholar]
  133. Bosques CJ, Imperiali B. 132.  2003. The interplay of glycosylation and disulfide formation influences fibrillization in a prion protein fragment. PNAS 100:7593–98 [Google Scholar]
  134. Hanson SR, Culyba EK, Hsu TL, Wong CH, Kelly JW, Powers ET. 133.  2009. The core trisaccharide of an N-linked glycoprotein intrinsically accelerates folding and enhances stability. PNAS 106:3131–36 [Google Scholar]
  135. Culyba EK, Price JL, Hanson SR, Dhar A, Wong CH. 134.  et al. 2011. Protein native-state stabilization by placing aromatic side chains in N-glycosylated reverse turns. Science 331:571–75 [Google Scholar]
  136. Chen W, Enck S, Price JL, Powers DL, Powers ET. 135.  et al. 2013. Structural and energetic basis of carbohydrate-aromatic packing interactions in proteins. J. Am. Chem. Soc. 135:9877–84 [Google Scholar]
  137. Bowden TA, Baruah K, Coles CH, Harvey DJ, Yu X. 136.  et al. 2012. Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis. J. Am. Chem. Soc. 134:17554–63 [Google Scholar]
  138. Chen MM, Bartlett AI, Nerenberg PS, Friel CT, Hackenberger CPR. 137.  et al. 2010. Perturbing the folding energy landscape of the bacterial immunity protein Im7 by site-specific N-linked glycosylation. PNAS 107:22528–33 [Google Scholar]
  139. Torres CR, Hart GW. 138.  1984. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes: evidence for O-linked GlcNAc. J. Biol. Chem. 259:3308–17 [Google Scholar]
  140. Ma J, Hart GW. 139.  2014. O-GlcNAc profiling: from proteins to proteomes. Clin. Proteom. 11:8 [Google Scholar]
  141. Bond MR, Hanover JA. 140.  2015. A little sugar goes a long way: the cell biology of O-GlcNAc. J. Cell Biol. 208:869–80 [Google Scholar]
  142. Simanek E, Huang D-H, Pasternack L, Machajewski T, Seitz O. 141.  et al. 1998. Glycosylation of threonine of the repeating unit of RNA polymerase II with β-linked N-acetylglucosame teads to a turnlike structure. J. Am. Chem. Soc. 120:11567–75 [Google Scholar]
  143. Chu CS, Lo PW, Yeh YH, Hsu PH, Peng SH. 142.  et al. 2014. O-GlcNAcylation regulates EZH2 protein stability and function. PNAS 111:1355–60 [Google Scholar]
  144. Schjoldager KT, Clausen H. 143.  2012. Site-specific protein O-glycosylation modulates proprotein processing—deciphering specific functions of the large polypeptide GalNAc-transferase gene family. Biochim. Biophys. Acta 1820:2079–94 [Google Scholar]
  145. Perez-Vilar J, Hill RL. 144.  1999. The structure and assembly of secreted mucins. J. Biol. Chem. 274:31751–54 [Google Scholar]
  146. Linden SK, Sutton P, Karlsson NG, Korolik V, McGuckin MA. 145.  2008. Mucins in the mucosal barrier to infection. Mucosal Immunol. 1:183–97 [Google Scholar]
  147. Tran DT, Ten Hagen KG. 146.  2013. Mucin-type O-glycosylation during development. J. Biol. Chem. 288:6921–29 [Google Scholar]
  148. Bennett EP, Mandel U, Clausen H, Gerken TA, Fritz TA, Tabak LA. 147.  2012. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology 22:736–56 [Google Scholar]
  149. Pratt MR, Hang HC, Ten Hagen KG, Rarick J, Gerken TA. 148.  et al. 2004. Deconvoluting the functions of polypeptide N-α-acetylgalactosaminyltransferase family members by glycopeptide substrate profiling. Chem. Biol. 11:1009–16 [Google Scholar]
  150. Ju T, Otto VI, Cummings RD. 149.  2011. The Tn antigen—structural simplicity and biological complexity. Angew. Chem. Int. Ed. Engl. 50:1770–91 [Google Scholar]
  151. Gaidzik N, Westerlind U, Kunz H. 150.  2013. The development of synthetic antitumour vaccines from mucin glycopeptide antigens. Chem. Soc. Rev. 42:4421–42 [Google Scholar]
  152. Sorensen AL, Reis CA, Tarp MA, Mandel U, Ramachandran K. 151.  et al. 2006. Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance. Glycobiology 16:96–107 [Google Scholar]
  153. DeFrees S, Wang ZG, Xing R, Scott AE, Wang J. 152.  et al. 2006. GlycoPEGylation of recombinant therapeutic proteins produced in Escherichia coli. Glycobiology 16:833–43 [Google Scholar]
  154. Lindhout T, Iqbal U, Willis LM, Reid AN, Li J. 153.  et al. 2011. Site-specific enzymatic polysialylation of therapeutic proteins using bacterial enzymes. PNAS 108:7397–402 [Google Scholar]
  155. Lingwood CA. 154.  2011. Glycosphingolipid functions. Cold Spring Harb. Perspect. Biol. 3:1–26 [Google Scholar]
  156. Wennekes T, van den Berg RJ, Boot RG, van der Marel GA, Overkleeft HS, Aerts JM. 155.  2009. Glycosphingolipids—nature, function, and pharmacological modulation. Angew. Chem. Int. Ed. Engl. 48:8848–69 [Google Scholar]
  157. Platt FM. 156.  2014. Sphingolipid lysosomal storage disorders. Nature 510:68–75 [Google Scholar]
  158. Lou YW, Wang PY, Yeh SC, Chuang PK, Li ST. 157.  et al. 2014. Stage-specific embryonic antigen-4 as a potential therapeutic target in glioblastoma multiforme and other cancers. PNAS 111:2482–87 [Google Scholar]
  159. Schnaar RL, Gerardy-Schahn R, Hildebrandt H. 158.  2014. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol. Rev. 94:461–518 [Google Scholar]
  160. Hancock SM, Rich JR, Caines ME, Strynadka NC, Withers SG. 159.  2009. Designer enzymes for glycosphingolipid synthesis by directed evolution. Nat. Chem. Biol. 5:508–14 [Google Scholar]
  161. Rich JR, Withers SG. 160.  2012. A chemoenzymatic total synthesis of the neurogenic starfish ganglioside LLG-3 using an engineered and evolved synthase. Angew. Chem. Int. Ed. Engl. 51:8640–43 [Google Scholar]
  162. Huang LY, Huang SH, Chang YC, Cheng WC, Cheng TJ, Wong CH. 161.  2014. Enzymatic synthesis of lipid II and analogues. Angew. Chem. Int. Ed. Engl. 53:8060–65 [Google Scholar]
  163. Yu S, Guo Z, Johnson C, Gu G, Wu Q. 162.  2013. Recent progress in synthetic and biological studies of GPI anchors and GPI-anchored proteins. Curr. Opin. Chem. Biol. 17:1006–13 [Google Scholar]
  164. Tsai Y-H, Liu X, Seeberger PH. 163.  2012. Chemical biology of glycosylphosphatidylinositol anchors. Angew. Chem. Int. Ed. Engl. 51:11438–56 [Google Scholar]
  165. Tsai YH, Grube M, Seeberger PH, Varón Silva D. 164.  2012. Glycosylphosphatidylinositols of protozoan parasites. Trends. Glycosci. Glycotechnol. 24:231–43 [Google Scholar]
  166. Paulick MG, Wise AR, Forstner MB, Groves JT, Bertozzi CR. 165.  2007. Synthetic analogues of glycosylphosphatidylinositol-anchored proteins and their behavior in supported lipid bilayers. J. Am. Chem. Soc. 129:11543–50 [Google Scholar]
  167. Becker CFW, Liu X, Olschewski D, Castelli R, Seidel R, Seeberger PH. 166.  2008. Semisynthesis of a glycosylphosphatidylinositol-anchored prion protein. Angew. Chem. Int. Ed. Engl. 47:8215–19 [Google Scholar]
  168. Schumacher MC, Resenberger U, Seidel RP, Becker CF, Winklhofer KF. 167.  et al. 2010. Synthesis of a GPI anchor module suitable for protein post-translational modification. Biopolymers 94:457–64 [Google Scholar]
  169. Guo X, Wang Q, Swarts BM, Guo Z. 168.  2009. Sortase-catalyzed peptide-glycosylphosphatidylinositol analogue ligation. J. Am. Chem. Soc. 131:9878–79 [Google Scholar]
  170. Wu Z, Guo X, Wang Q, Swarts BM, Guo Z. 169.  2010. Sortase A-catalyzed transpeptidation of glycosylphosphatidylinositol derivatives for chemoenzymatic synthesis of GPI-anchored proteins. J. Am. Chem. Soc. 132:1567–71 [Google Scholar]
  171. Hakomori S. 170.  2001. Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines. Adv. Exp. Med. Biol. 491:369–402 [Google Scholar]
  172. Wilson RM, Danishefsky SJ. 171.  2013. A vision for vaccines built from fully synthetic tumor-associated antigens: from the laboratory to the clinic. J. Am. Chem. Soc. 135:14462–72 [Google Scholar]
  173. Yin Z, Huang X. 172.  2012. Recent development in carbohydrate based anti-cancer vaccines. J. Carbohydr. Chem. 31:143–86 [Google Scholar]
  174. Huang YL, Hung JT, Cheung SK, Lee HY, Chu KC. 173.  et al. 2013. Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer. PNAS 110:2517–22 [Google Scholar]
  175. Hung TC, Lin CW, Hsu TL, Wu CY, Wong CH. 174.  2013. Investigation of SSEA-4 binding protein in breast cancer cells. J. Am. Chem. Soc. 135:5934–37 [Google Scholar]
  176. Lee HY, Chen CY, Tsai TI, Li ST, Lin KH. 175.  et al. 2014. Immunogenicity study of Globo H analogues with modification at the reducing or nonreducing end of the tumor antigen. J. Am. Chem. Soc. 136:16844–53 [Google Scholar]
  177. Danishefsky SJ, Shue YK, Chang MN, Wong CH. 176.  2015. Development of Globo-H cancer vaccine. Acc. Chem. Res. 48:643–52 [Google Scholar]
  178. Rillahan CD, Paulson JC. 177.  2011. Glycan microarrays for decoding the glycome. Annu. Rev. Biochem. 80:797–823 [Google Scholar]

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