CMP-Sialic Acid Synthetase: The Point of Constriction in the Sialylation Pathway

  • Melanie Sellmeier
  • Birgit Weinhold
  • Anja Münster-Kühnel
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 366)


Sialoglycoconjugates form the outermost layer of animal cells and play a crucial role in cellular communication processes. An essential step in the biosynthesis of sialylated glycoconjugates is the activation of sialic acid to the monophosphate diester CMP-sialic acid. Only the activated sugar is transported into the Golgi apparatus and serves as a substrate for the linkage-specific sialyltransferases. Interference with sugar activation abolishes sialylation and is embryonic lethal in mammals. In this chapter we focus on the enzyme catalyzing the activation of sialic acid, the CMP-sialic acid synthetase (CMAS), and compare the enzymatic properties of CMASs isolated from different species. Information concerning the reaction mechanism and active site architecture is included. Moreover, the unusual nuclear localization of vertebrate CMASs as well as the biotechnological application of bacterial CMAS enzymes is addressed.


CMP-sialic acid synthetase N-Acetyl-neuraminic acid Sialic acid Sialoside 



CMAS from Branchiostoma belcheri


CMAS from Bos taurus


CMP-3-deoxy-d-manno-octulosonic acid synthetase


Cytidine monophosphate N-acetylneuraminic acid synthetase


CMAS from Clostridium thermocellum


CMAS from Drosophila melanogaster


CMAS from Danio rerio


CMAS from Escherichia coli


CMAS from Haemophilus ducreyi


Deaminated neuraminic acid


3-Deoxy-d-manno-octulosonic acid


CMAS from Mannheimia haemolytica


CMAS from Mus musculus


N-Acetyl-neuraminic acid


N-Glycolyl-neuraminic acid


CMAS from Neisseria meningitidis


CMAS from Oncorhynchus mykiss


Platelet-activating factor acetylhydrolase


CMAS from Pasteurella multocida


CMAS from Streptococcus agalactiae


Sialic acid


CMAS from Streptococcus suis


  1. 1.
    Kean EL (1991) Sialic acid activation. Glycobiology 1:441–447Google Scholar
  2. 2.
    Potvin B, Raju TS, Stanley P (1995) Lec32 is a new mutation in Chinese hamster ovary cells that essentially abrogates CMP-N-acetylneuraminic acid synthetase activity. J Biol Chem 270:30415–30421Google Scholar
  3. 3.
    Münster AK, Eckhardt M, Potvin B, Mühlenhoff M, Stanley P, Gerardy-Schahn R (1998) Mammalian cytidine 5′-monophosphate N-acetylneuraminic acid synthetase: a nuclear protein with evolutionarily conserved structural motifs. Proc Natl Acad Sci USA 95:9140–9145Google Scholar
  4. 4.
    Vimr ER, Troy FA (1985) Regulation of sialic acid metabolism in Escherichia coli: role of N-acylneuraminate pyruvate-lyase. J Bacteriol 164:854–860Google Scholar
  5. 5.
    Weinhold B, Sellmeier M, Schaper W, Blume L, Philippens B, Kats E, Bernard U, Galuska SP, Geyer H, Geyer R, Worthmann K, Schiffer M, Groos S, Gerardy-Schahn R, Münster-Kühnel AK (2012) Deficits in sialylation impair podocyte maturation. J Am Soc Nephrol 23:1319–1328Google Scholar
  6. 6.
    Varki NM, Varki A (2007) Diversity in cell surface sialic acid presentations: implications for biology and disease. Lab Invest 87:851–857Google Scholar
  7. 7.
    Hildebrandt H, Mühlenhoff M, Weinhold B, Gerardy-Schahn R (2007) Dissecting polysialic acid and NCAM functions in brain development. J Neurochem 103(Suppl 1):56–64Google Scholar
  8. 8.
    Lehmann F, Tiralongo E, Tiralongo J (2006) Sialic acid-specific lectins: occurrence, specificity and function. Cell Mol Life Sci 63:1331–1354Google Scholar
  9. 9.
    Hildebrand H, Dityatev A (2013) Polysialic acid in brain development and synaptic plasticity. Top Curr Chem. doi:10.1007/128_2013_446 Google Scholar
  10. 10.
    Ginsburg V (1964) Sugar nucleotides and the synthesis of carbohydrates. Adv Enzymol Relat Areas Mol Biol 26:35–88Google Scholar
  11. 11.
    Comb DG, Watson DR, Roseman S (1966) The sialic acids. IX. Isolation of cytidine 5′-monophospho-N-acetylneuraminic acid from Escherichia coli K-235. J Biol Chem 241:5637–5642Google Scholar
  12. 12.
    Kajihara Y, Nishigaki S, Hanzawa D, Nakanishi G, Okamoto R, Yamamoto N (2011) Unique self-anhydride formation in the degradation of cytidine-5′-monophosphosialic acid (CMP-Neu5Ac) and cytidine-5′-diphosphosialic acid (CDP-Neu5Ac) and its application in CMP-sialic acid analogue synthesis. Chemistry 17:7645–7655Google Scholar
  13. 13.
    Kornfeld S, Neufeld EF, Obrien PJ, Kornfeld R (1964) Feedback control of sugar nucleotide biosynthesis in liver. Proc Natl Acad Sci USA 52:371–379Google Scholar
  14. 14.
    Hinderlich S, Weidemann W, Yardeni T, Horstkorte R, Huizing M (2013) UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), a master regulator of sialic acid synthesis. Top Curr Chem. doi:10.1007/128_2013_464 Google Scholar
  15. 15.
    Vimr ER, Kalivoda KA, Deszo EL, Steenbergen SM (2004) Diversity of microbial sialic acid metabolism. Microbiol Mol Biol Rev 68:132–153Google Scholar
  16. 16.
    Vimr E, Lichtensteiger C (2002) To sialylate, or not to sialylate: that is the question. Trends Microbiol 10:254–257Google Scholar
  17. 17.
    Severi E, Hood DW, Thomas GH (2007) Sialic acid utilization by bacterial pathogens. Microbiology 153:2817–2822Google Scholar
  18. 18.
    Comb DG, Shimizu F, Roseman S (1959) Isolation of cytidine-5′-monophosphate-N-acetylneuraminic acid. J Am Chem Soc 81:5513–5514Google Scholar
  19. 19.
    Warren L, Blacklow RS (1962) The biosynthesis of cytidine 5′-monophospho-n-acetylneuraminic acid by an enzyme from Neisseria meningitidis. J Biol Chem 237:3527–3534Google Scholar
  20. 20.
    Roseman S (1962) Enzymatic synthesis of cytidine 5′-mono-phospho-sialic acids. Proc Natl Acad Sci USA 48:437–441Google Scholar
  21. 21.
    Shoyab M, Pattabiraman TN, Bachhawat BK (1964) Purification and properties of the cmp-N-acetylneuraminic acid synthesizing enzyme from sheep brain. J Neurochem 11:639–646Google Scholar
  22. 22.
    Kean EL, Roseman S (1966) The sialic acids. X. Purification and properties of cytidine 5′-monophosphosialic acid synthetase. J Biol Chem 241:5643–5650Google Scholar
  23. 23.
    Hultsch E, Reutter W, Kecker K (1972) Conversion of N-acetylglucosamine to CMP-N-acetyl-neuraminic acid in a cell-free system of rat liver. Biochim Biophys Acta 273:132–140Google Scholar
  24. 24.
    Schauer R, Haverkamp J, Ehrlich K (1980) Isolation and characterization of acylneuraminate cytidylyltransferase from frog liver. Hoppe Seylers Z Physiol Chem 361:641–648Google Scholar
  25. 25.
    Kajiwara H, Mine T, Miyazaki T, Yamamoto T (2011) A CMP-N-acetylneuraminic acid synthetase purified from a marine bacterium, Photobacterium leiognathi JT-SHIZ-145. Biosci Biotechnol Biochem 75:47–53Google Scholar
  26. 26.
    Zapata G, Vann WF, Aaronson W, Lewis MS, Moos M (1989) Sequence of the cloned Escherichia coli K1 CMP-N-acetylneuraminic acid synthetase gene. J Biol Chem 264:14769–14774Google Scholar
  27. 27.
    Edwards U, Frosch M (1992) Sequence and functional analysis of the cloned Neisseria meningitidis CMP-NeuNAc synthetase. FEMS Microbiol Lett 75:161–166Google Scholar
  28. 28.
    Haft RF, Wessels MR (1994) Characterization of CMP-N-acetylneuraminic acid synthetase of group B streptococci. J Bacteriol 176:7372–7374Google Scholar
  29. 29.
    Tullius MV, Munson RS Jr, Wang J, Gibson BW (1996) Purification, cloning, and expression of a cytidine 5′-monophosphate N-acetylneuraminic acid synthetase from Haemophilus ducreyi. J Biol Chem 271:15373–15380Google Scholar
  30. 30.
    Ishige K, Hamamoto T, Shiba T, Noguchi T (2001) Novel method for enzymatic synthesis of CMP-NeuAc. Biosci Biotechnol Biochem 65:1736–1740Google Scholar
  31. 31.
    Mizanur RM, Pohl NL (2007) Cloning and characterization of a heat-stable CMP-N-acylneuraminic acid synthetase from Clostridium thermocellum. Appl Microbiol Biotechnol 76:827–834Google Scholar
  32. 32.
    Song L, Zhou H, Cai X, Li C, Liang J, Jin C (2011) NeuA O-acetylesterase activity is specific for CMP-activated O-acetyl sialic acid in Streptococcus suis serotype 2. Biochem Biophys Res Commun 410:212–217Google Scholar
  33. 33.
    Li Y, Yu H, Cao H, Muthana S, Chen X (2012) Pasteurella multocida CMP-sialic acid synthetase and mutants of Neisseria meningitidis CMP-sialic acid synthetase with improved substrate promiscuity. Appl Microbiol Biotechnol 93:2411–2423Google Scholar
  34. 34.
    Nakata D, Münster AK, Gerardy-Schahn R, Aoki N, Matsuda T, Kitajima K (2001) Molecular cloning of a unique CMP-sialic acid synthetase that effectively utilizes both deaminoneuraminic acid (KDN) and N-acetylneuraminic acid (Neu5Ac) as substrates. Glycobiology 11:685–692Google Scholar
  35. 35.
    Lawrence SM, Huddleston KA, Tomiya N, Nguyen N, Lee YC, Vann WF, Coleman TA, Betenbaugh MJ (2001) Cloning and expression of human sialic acid pathway genes to generate CMP-sialic acids in insect cells. Glycoconj J 18:205–213Google Scholar
  36. 36.
    Schaper W, Bentrop J, Ustinova J, Blume L, Kats E, Tiralongo J, Weinhold B, Bastmeyer M, Münster-Kühnel AK (2012) Identification and biochemical characterization of two functional CMP-sialic acid synthetases in Danio rerio. J Biol Chem 287:13239–13248Google Scholar
  37. 37.
    Guerardel Y, Chang LY, Fujita A, Coddeville B, Maes E, Sato C, Harduin-Lepers A, Kubokawa K, Kitajima K (2012) Sialome analysis of the cephalochordate Branchiostoma belcheri, a key organism for vertebrate evolution. Glycobiology 22:479–491Google Scholar
  38. 38.
    Viswanathan K, Tomiya N, Park J, Singh S, Lee YC, Palter K, Betenbaugh MJ (2006) Expression of a functional Drosophila melanogaster CMP-sialic acid synthetase. Differential localization of the Drosophila and human enzymes. J Biol Chem 281:15929–15940Google Scholar
  39. 39.
    Münster-Kühnel AK, Tiralongo J, Krapp S, Weinhold B, Ritz-Sedlacek V, Jacob U, Gerardy-Schahn R (2004) Structure and function of vertebrate CMP-sialic acid synthetases. Glycobiology 14:43R–51RGoogle Scholar
  40. 40.
    Angata T, Varki A (2002) Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem Rev 102:439–469Google Scholar
  41. 41.
    Lepers A, Shaw L, Schneckenburger P, Cacan R, Verbert A, Schauer R (1990) A study on the regulation of N-glycoloylneuraminic acid biosynthesis and utilization in rat and mouse liver. Eur J Biochem 193:715–723Google Scholar
  42. 42.
    Davies LRL, Varki A (2013) Why is N-glycolylneuraminic acid rare in the vertebrate brain? Top Curr Chem. doi:10.1007/128_2013_419 Google Scholar
  43. 43.
    Traving C, Schauer R (1998) Structure, function and metabolism of sialic acids. Cell Mol Life Sci 54:1330–1349Google Scholar
  44. 44.
    Bravo IG, Garcia-Vallve S, Romeu A, Reglero A (2004) Prokaryotic origin of cytidylyltransferases and alpha-ketoacid synthases. Trends Microbiol 12:120–128Google Scholar
  45. 45.
    Inoue S, Kitajima K (2006) KDN (deaminated neuraminic acid): dreamful past and exciting future of the newest member of the sialic acid family. Glycoconj J 23:277–290Google Scholar
  46. 46.
    Mizanur RM, Pohl NL (2008) Bacterial CMP-sialic acid synthetases: production, properties, and applications. Appl Microbiol Biotechnol 80:757–765Google Scholar
  47. 47.
    Bravo IG, Barrallo S, Ferrero MA, Rodriguez-Aparicio LB, Martinez-Blanco H, Reglero A (2001) Kinetic properties of the acylneuraminate cytidylyltransferase from Pasteurella haemolytica A2. Biochem J 358:585–598Google Scholar
  48. 48.
    Blixt O, Paulson JC (2003) Biocatalytic preparation of N-glycolylneuraminic acid, deaminoneuraminic acid (KDN) and 9-azido-9-deoxysialic acid oligosaccharides. Adv Synth Catal 345:687–690Google Scholar
  49. 49.
    Yu H, Yu H, Karpel R, Chen X (2004) Chemoenzymatic synthesis of CMP-sialic acid derivatives by a one-pot two-enzyme system: comparison of substrate flexibility of three microbial CMP-sialic acid synthetases. Bioorg Med Chem 12:6427–6435Google Scholar
  50. 50.
    Knorst M, Fessner W-D (2001) CMP-sialate synthetase from Neisseria meningitidis – overexpression and application to the synthesis of oligosaccharides containing modified sialic acids. Adv Synth Catal 343:698–710Google Scholar
  51. 51.
    Hartlieb S, Gunzel A, Gerardy-Schahn R, Munster-Kuhnel AK, Kirschning A, Drager G (2008) Chemoenzymatic synthesis of CMP-N-acetyl-7-fluoro-7-deoxy-neuraminic acid. Carbohydr Res 343:2075–2082Google Scholar
  52. 52.
    Morley TJ, Withers SG (2010) Chemoenzymatic synthesis and enzymatic analysis of 8-modified cytidine monophosphate-sialic acid and sialyl lactose derivatives. J Am Chem Soc 132:9430–9437Google Scholar
  53. 53.
    Shames SL, Simon ES, Christopher CW, Schmid W, Whitesides GM, Yang LL (1991) CMP-N-acetylneuraminic acid synthetase of Escherichia coli: high level expression, purification and use in the enzymatic synthesis of CMP-N-acetylneuraminic acid and CMP-neuraminic acid derivatives. Glycobiology 1:187–191Google Scholar
  54. 54.
    Liu JL, Shen G-J, Ichikawa Y, Rutan F, Zapata G, Vann WF, Wong C-H (1992) Overproduction of CMP-sialic acid synthetase for organic synthesis. J Am Chem Soc 114:3901–3910Google Scholar
  55. 55.
    Terada T, Kitazume S, Kitajima K, Inoue S, Ito F, Troy FA, Inoue Y (1993) Synthesis of CMP-deaminoneuraminic acid (CMP-KDN) using the CTP:CMP-3-deoxynonulosonate cytidylyltransferase from rainbow trout testis Identification and characterization of a CMP-KDN synthetase. J Biol Chem 268:2640–2648Google Scholar
  56. 56.
    Terada T, Kitajima K, Inoue S, Koppert K, Brossmer R, Inoue Y (1996) Substrate specificity of rainbow trout testis CMP-3-deoxy-d-glycero-d-galacto-nonulosonic acid (CMP-Kdn) synthetase: kinetic studies of the reaction of natural and synthetic analogues of nonulosonic acid catalyzed by CMP-Kdn synthetase. Eur J Biochem 236:852–855Google Scholar
  57. 57.
    Gross HJ, Brossmer R (1987) N-Acetyl-4-deoxy-d-neuraminic acid is activated and transferred on to asialoglycoprotein. Glycoconj J 4:145–156Google Scholar
  58. 58.
    Gross HJ, Bunsch A, Paulson JC, Brossmer R (1987) Activation and transfer of novel synthetic 9-substituted sialic acids. Eur J Biochem 168:595–602Google Scholar
  59. 59.
    Gross HJ, Brossmer R (1995) Enzymatic transfer of sialic acids modified at C-5 employing four different sialyltransferases. Glycoconj J 12:739–746Google Scholar
  60. 60.
    Isecke R, Brossmer R (1994) Synthesis of 5-N- and 9-N-thioacylated sialic acids. Tetrahedron 50:7445–7460Google Scholar
  61. 61.
    Wong JH, Sahni U, Li Y, Chen X, Gervay-Hague J (2009) Synthesis of sulfone-based nucleotide isosteres: identification of CMP-sialic acid synthetase inhibitors. Org Biomol Chem 7:27–29Google Scholar
  62. 62.
    Rodriguez-Aparicio LB, Luengo JM, Gonzalez-Clemente C, Reglero A (1992) Purification and characterization of the nuclear cytidine 5′-monophosphate N-acetylneuraminic acid synthetase from rat liver. J Biol Chem 267:9257–9263Google Scholar
  63. 63.
    Petrie CR III, Korytnyk W (1983) A high-performance liquid chromatography method for the assay of cytidine monophosphate-sialic acid synthetase. Anal Biochem 131:153–159Google Scholar
  64. 64.
    Horsfall LE, Nelson A, Berry A (2010) Identification and characterization of important residues in the catalytic mechanism of CMP-Neu5Ac synthetase from Neisseria meningitidis. FEBS J 277:2779–2790Google Scholar
  65. 65.
    Mosimann SC, Gilbert M, Dombroswki D, To R, Wakarchuk W, Strynadka NC (2001) Structure of a sialic acid-activating synthetase, CMP-acylneuraminate synthetase in the presence and absence of CDP. J Biol Chem 276:8190–8196Google Scholar
  66. 66.
    Krapp S, Münster-Kühnel AK, Kaiser JT, Huber R, Tiralongo J, Gerardy-Schahn R, Jacob U (2003) The crystal structure of murine CMP-5-N-acetylneuraminic acid synthetase. J Mol Biol 334:625–637Google Scholar
  67. 67.
    Münster AK, Weinhold B, Gotza B, Mühlenhoff M, Frosch M, Gerardy-Schahn R (2002) Nuclear localization signal of murine CMP-Neu5Ac synthetase includes residues required for both nuclear targeting and enzymatic activity. J Biol Chem 277:19688–19696Google Scholar
  68. 68.
    Cipolla L, Gabrielli L, Bini D, Russo L, Shaikh N (2010) Kdo: a critical monosaccharide for bacteria viability. Nat Prod Rep 27:1618–1629Google Scholar
  69. 69.
    Royo J, Gomez E, Hueros G (2000) A maize homologue of the bacterial CMP-3-deoxy-d-manno-2-octulosonate (KDO) synthetases. Similar pathways operate in plants and bacteria for the activation of KDO prior to its incorporation into outer cellular envelopes. J Biol Chem 275:24993–24999Google Scholar
  70. 70.
    Heyes DJ, Levy C, Lafite P, Roberts IS, Goldrick M, Stachulski AV, Rossington SB, Stanford D, Rigby SE, Scrutton NS, Leys D (2009) Structure-based mechanism of CMP-2-keto-3-deoxymanno-octulonic acid synthetase: convergent evolution of a sugar-activating enzyme with DNA/RNA polymerases. J Biol Chem 284:35514–35523Google Scholar
  71. 71.
    Jelakovic S, Schulz GE (2001) The structure of CMP:2-keto-3-deoxy-manno-octonic acid synthetase and of its complexes with substrates and substrate analogs. J Mol Biol 312:143–155Google Scholar
  72. 72.
    Oschlies M, Dickmanns A, Haselhorst T, Schaper W, Stummeyer K, Tiralongo J, Weinhold B, Gerardy-Schahn R, von Itzstein M, Ficner R, Münster-Kühnel AK (2009) A C-terminal phosphatase module conserved in vertebrate CMP-sialic acid synthetases provides a tetramerization interface for the physiologically active enzyme. J Mol Biol 393:83–97Google Scholar
  73. 73.
    Dorland L, Haverkamp J, Schauer R, Veldink GA, Vliegenthart JF (1982) The preparation of specifically deuterium- or tritium-labeled N-acetylneuraminic acid and cytidine-5′-monophospho-beta-N-acetylneuraminic acid as precursors for glycoconjugate synthesis. Biochem Biophys Res Commun 104:1114–1119Google Scholar
  74. 74.
    Ambrose MG, Freese SJ, Reinhold MS, Warner TG, Vann WF (1992) 13C NMR investigation of the anomeric specificity of CMP-N-acetylneuraminic acid synthetase from Escherichia coli. Biochemistry 31:775–780Google Scholar
  75. 75.
    Haverkamp J, Spoormaker T, Dorland L, Vliegenthart JF, Schauer R (1979) Determination of the b-anomeric configuration of cytidine 5′-monophospho-N-acetylneuraminic acid by 13C NMR spectroscopy. J Am Chem Soc 101:4851–4853Google Scholar
  76. 76.
    Samuels NM, Gibson BW, Miller SM (1999) Investigation of the kinetic mechanism of cytidine 5′-monophosphate N-acetylneuraminic acid synthetase from Haemophilus ducreyi with new insights on rate-limiting steps from product inhibition analysis. Biochemistry 38:6195–6203Google Scholar
  77. 77.
    Tullius MV, Vann WF, Gibson BW (1999) Covalent modification of Lys19 in the CTP binding site of cytidine 5′-monophosphate N-acetylneuraminic acid synthetase. Protein Sci 8:666–675Google Scholar
  78. 78.
    Stoughton DM, Zapata G, Picone R, Vann WF (1999) Identification of Arg-12 in the active site of Escherichia coli K1 CMP-sialic acid synthetase. Biochem J 343(Pt 2):397–402Google Scholar
  79. 79.
    Haselhorst T, Münster-Kühnel AK, Stolz A, Oschlies M, Tiralongo J, Kitajima K, Gerardy-Schahn R, von Itzstein M (2005) Probing a CMP-Kdn synthetase by 1H, 31P, and STD NMR spectroscopy. Biochem Biophys Res Commun 327:565–570Google Scholar
  80. 80.
    Jelakovic S, Schulz GE (2002) Catalytic mechanism of CMP:2-keto-3-deoxy-manno-octonic acid synthetase as derived from complexes with reaction educt and product. Biochemistry 41:1174–1181Google Scholar
  81. 81.
    Kean EL, Münster-Kühnel AK, Gerardy-Schahn R (2004) CMP-sialic acid synthetase of the nucleus. Biochim Biophys Acta 1673:56–65Google Scholar
  82. 82.
    Kean EL (1969) Sialic acid activating enzyme in ocular tissue. Exp Eye Res 8:44–54Google Scholar
  83. 83.
    Gielen W, Schaper R, Pink H (1971) Subcellular distribution and activity of cytidinemonophospho-N-acetylneuraminate-synthetase in the young rat brain. Hoppe Seylers Z Physiol Chem 352:1291–1296Google Scholar
  84. 84.
    van Dijk W, Ferwerda W, van den Eijnden DH (1973) Subcellular and regional distribution of CMP-N-acetylneuraminic acid synthetase in the calf kidney. Biochim Biophys Acta 315:162–175Google Scholar
  85. 85.
    Tiralongo J, Fujita A, Sato C, Kitajima K, Lehmann F, Oschlies M, Gerardy-Schahn R, Münster-Kühnel AK (2007) The rainbow trout CMP-sialic acid synthetase utilises a nuclear localization signal different from that identified in the mouse enzyme. Glycobiology 17:945–954Google Scholar
  86. 86.
    Terry LJ, Shows EB, Wente SR (2007) Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science 318:1412–1416Google Scholar
  87. 87.
    Nigg EA (1997) Nucleocytoplasmic transport: signals, mechanisms and regulation. Nature 386:779–787Google Scholar
  88. 88.
    Sorokin AV, Kim ER, Ovchinnikov LP (2007) Nucleocytoplasmic transport of proteins. Biochemistry (Mosc) 72:1439–1457Google Scholar
  89. 89.
    Christophe D, Christophe-Hobertus C, Pichon B (2000) Nuclear targeting of proteins: how many different signals? Cell Signal 12:337–341Google Scholar
  90. 90.
    Fujita A, Sato C, Kitajima K (2007) Identification of the nuclear export signals that regulate the intracellular localization of the mouse CMP-sialic acid synthetase. Biochem Biophys Res Commun 355:174–180Google Scholar
  91. 91.
    Koles K, Repnikova E, Pavlova G, Korochkin LI, Panin VM (2009) Sialylation in protostomes: a perspective from Drosophila genetics and biochemistry. Glycoconj J 26:313–324Google Scholar
  92. 92.
    Macdougall IC (2002) Optimizing the use of erythropoietic agents – pharmacokinetic and pharmacodynamic considerations. Nephrol Dial Transplant 17(Suppl 5):66–70Google Scholar
  93. 93.
    Fukuda MN, Sasaki H, Lopez L, Fukuda M (1989) Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood 73:84–89Google Scholar
  94. 94.
    Stockert RJ (1995) The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 75:591–609Google Scholar
  95. 95.
    Sethuraman N, Stadheim TA (2006) Challenges in therapeutic glycoprotein production. Curr Opin Biotechnol 17:341–346Google Scholar
  96. 96.
    Danishefsky SJ, DeNinno MP, Chen S-H (1988) Stereoselective total syntheses of the naturally occurring enantiomers of N-acetylneuraminic acid and 3-deoxy-d-manno-2-octuloson acid. A new and stereospecific approach to sialo and 3-deoxy-d-manno-2-octuloson acid conjugates. J Am Chem Soc 110:3929–3940Google Scholar
  97. 97.
    Li LS, Wu YL, Wu Y (2000) Total synthesis of fully acetylated N-acetylneuraminic acid (Neu5Ac), 2-deoxy-beta-Neu5Ac, and 4-epi-2-deoxy-beta-Neu5Ac from d-glucose. Org Lett 2:891–894Google Scholar
  98. 98.
    Boons GJ, Demchenko AV (2000) Recent advances in O-sialylation. Chem Rev 100:4539–4566Google Scholar
  99. 99.
    Kiefel MJ, von Itzstein M (2002) Recent advances in the synthesis of sialic acid derivatives and sialylmimetics as biological probes. Chem Rev 102:471–490Google Scholar
  100. 100.
    Halcomb RL, Chappell MD (2002) Recent developments in technology for glycosylation with sialic acid. J Carbohydr Chem 21:723–768Google Scholar
  101. 101.
    Chen X, Varki A (2010) Advances in the biology and chemistry of sialic acids. ACS Chem Biol 5:163–176Google Scholar
  102. 102.
    Gilbert M, Bayer R, Cunningham AM, DeFrees S, Gao Y, Watson DC, Young NM, Wakarchuk WW (1998) The synthesis of sialylated oligosaccharides using a CMP-Neu5Ac synthetase/sialyltransferase fusion. Nat Biotechnol 16:769–772Google Scholar
  103. 103.
    Yu CC, Lin PC, Lin CC (2008) Site-specific immobilization of CMP-sialic acid synthetase on magnetic nanoparticles and its use in the synthesis of CMP-sialic acid. Chem Commun (Camb) 11:1308–1310Google Scholar
  104. 104.
    Yu CC, Kuo YY, Liang CF, Chien WT, Wu HT, Chang TC, Jan FD, Lin CC (2012) Site-specific immobilization of enzymes on magnetic nanoparticles and their use in organic synthesis. Bioconjug Chem 23:714–724Google Scholar
  105. 105.
    Saint-Jore-Dupas C, Faye L, Gomord V (2007) From planta to pharma with glycosylation in the toolbox. Trends Biotechnol 25:317–323Google Scholar
  106. 106.
    Ma JK, Hiatt A, Hein M, Vine ND, Wang F, Stabila P, van Dolleweerd C, Mostov K, Lehner T (1995) Generation and assembly of secretory antibodies in plants. Science 268:716–719Google Scholar
  107. 107.
    Seveno M, Bardor M, Paccalet T, Gomord V, Lerouge P, Faye L (2004) Glycoprotein sialylation in plants? Nat Biotechnol 22:1351–1352Google Scholar
  108. 108.
    Zeleny R, Leonard R, Dorfner G, Dalik T, Kolarich D, Altmann F (2006) Molecular cloning and characterization of a plant alpha1, 3/4-fucosidase based on sequence tags from almond fucosidase I. Phytochemistry 67:641–648Google Scholar
  109. 109.
    Koprivova A, Stemmer C, Altmann F, Hoffmann A, Kopriva S, Gorr G, Reski R, Decker EL (2004) Targeted knockouts of Physcomitrella lacking plant-specific immunogenic N-glycans. Plant Biotechnol J 2:517–523Google Scholar
  110. 110.
    Strasser R, Altmann F, Glossl J, Steinkellner H (2004) Unaltered complex N-glycan profiles in Nicotiana benthamiana despite drastic reduction of beta1, 2-N-acetylglucosaminyltransferase I activity. Glycoconj J 21:275–282Google Scholar
  111. 111.
    Strasser R, Stadlmann J, Schahs M, Stiegler G, Quendler H, Mach L, Glossl J, Weterings K, Pabst M, Steinkellner H (2008) Generation of glyco-engineered Nicotiana benthamiana for the production of monoclonal antibodies with a homogeneous human-like N-glycan structure. Plant Biotechnol J 6:392–402Google Scholar
  112. 112.
    Cox KM, Sterling JD, Regan JT, Gasdaska JR, Frantz KK, Peele CG, Black A, Passmore D, Moldovan-Loomis C, Srinivasan M, Cuison S, Cardarelli PM, Dickey LF (2006) Glycan optimization of a human monoclonal antibody in the aquatic plant Lemna minor. Nat Biotechnol 24:1591–1597Google Scholar
  113. 113.
    Schahs M, Strasser R, Stadlmann J, Kunert R, Rademacher T, Steinkellner H (2007) Production of a monoclonal antibody in plants with a humanized N-glycosylation pattern. Plant Biotechnol J 5:657–663Google Scholar
  114. 114.
    Castilho A, Pabst M, Leonard R, Veit C, Altmann F, Mach L, Glossl J, Strasser R, Steinkellner H (2008) Construction of a functional CMP-sialic acid biosynthesis pathway in Arabidopsis. Plant Physiol 147:331–339Google Scholar
  115. 115.
    Chaffin DO, McKinnon K, Rubens CE (2002) CpsK of Streptococcus agalactiae exhibits alpha2,3-sialyltransferase activity in Haemophilus ducreyi. Mol Microbiol 45:109–122Google Scholar
  116. 116.
    Van Calsteren MR, Gagnon F, Lacouture S, Fittipaldi N, Gottschalk M (2010) Structure determination of Streptococcus suis serotype 2 capsular polysaccharide. Biochem Cell Biol 88:513–525Google Scholar
  117. 117.
    McGuire EJ, Binkley SB (1964) The structure and chemistry of colominic acid. Biochemistry 3:247–251Google Scholar
  118. 118.
    Frasa H, Procee J, Torensma R, Verbruggen A, Algra A, Rozenberg-Arska M, Kraaijeveld K, Verhoef J (1993) Escherichia coli in bacteremia: O-acetylated K1 strains appear to be more virulent than non-O-acetylated K1 strains. J Clin Microbiol 31:3174–3178Google Scholar
  119. 119.
    Lewis AL, Nizet V, Varki A (2004) Discovery and characterization of sialic acid O-acetylation in group B Streptococcus. Proc Natl Acad Sci USA 101:11123–11128Google Scholar
  120. 120.
    Deszo EL, Steenbergen SM, Freedberg DI, Vimr ER (2005) Escherichia coli K1 polysialic acid O-acetyltransferase gene, neuO, and the mechanism of capsule form variation involving a mobile contingency locus. Proc Natl Acad Sci USA 102:5564–5569Google Scholar
  121. 121.
    Carlin AF, Lewis AL, Varki A, Nizet V (2007) Group B streptococcal capsular sialic acids interact with siglecs (immunoglobulin-like lectins) on human leukocytes. J Bacteriol 189:1231–1237Google Scholar
  122. 122.
    Vlasak R et al. (2013) Functions and biosynthesis of O-acetylated sialic acids. Top Curr Chem. doi:10.1007/128_2011_310 Google Scholar
  123. 123.
    Yu H, Ryan W, Yu H, Chen X (2006) Characterization of a bifunctional cytidine 5′-monophosphate N-acetylneuraminic acid synthetase cloned from Streptococcus agalactiae. Biotechnol Lett 28:107–113Google Scholar
  124. 124.
    Steenbergen SM, Lee YC, Vann WF, Vionnet J, Wright LF, Vimr ER (2006) Separate pathways for O acetylation of polymeric and monomeric sialic acids and identification of sialyl O-acetyl esterase in Escherichia coli K1. J Bacteriol 188:6195–6206Google Scholar
  125. 125.
    Liu G, Jin C, Jin C (2004) CMP-N-acetylneuraminic acid synthetase from Escherichia coli K1 is a bifunctional enzyme: identification of minimal catalytic domain for synthetase activity and novel functional domain for platelet-activating factor acetylhydrolase activity. J Biol Chem 279:17738–17749Google Scholar
  126. 126.
    Ganguli S, Zapata G, Wallis T, Reid C, Boulnois G, Vann WF, Roberts IS (1994) Molecular cloning and analysis of genes for sialic acid synthesis in Neisseria meningitidis group B and purification of the meningococcal CMP-NeuNAc synthetase enzyme. J Bacteriol 176:4583–4589Google Scholar
  127. 127.
    Kelley LA, Sternberg MJ (2009) Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc 4:363–371Google Scholar
  128. 128.
    Lewis AL, Cao H, Patel SK, Diaz S, Ryan W, Carlin AF, Thon V, Lewis WG, Varki A, Chen X, Nizet V (2007) NeuA sialic acid O-acetylesterase activity modulates O-acetylation of capsular polysaccharide in group B Streptococcus. J Biol Chem 282:27562–27571Google Scholar
  129. 129.
    Parsons JF, Lim K, Tempczyk A, Krajewski W, Eisenstein E, Herzberg O (2002) From structure to function: YrbI from Haemophilus influenzae (HI1679) is a phosphatase. Proteins 46:393–404Google Scholar
  130. 130.
    Allen KN, Dunaway-Mariano D (2004) Phosphoryl group transfer: evolution of a catalytic scaffold. Trends Biochem Sci 29:495–503Google Scholar
  131. 131.
    Burroughs AM, Allen KN, Dunaway-Mariano D, Aravind L (2006) Evolutionary genomics of the HAD superfamily: understanding the structural adaptations and catalytic diversity in a superfamily of phosphoesterases and allied enzymes. J Mol Biol 361:1003–1034Google Scholar
  132. 132.
    Vionnet J, Concepcion N, Warner T, Zapata G, Hanover J, Vann WF (1999) Purification of CMP-N-acetylneuraminic acid synthetase from bovine anterior pituitary glands. Glycobiology 9:481–487Google Scholar
  133. 133.
    Rauvolfova J, Venot A, Boons GJ (2008) Chemo-enzymatic synthesis of C-9 acetylated sialosides. Carbohydr Res 343:1605–1611Google Scholar
  134. 134.
    Corpet F (1988) Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res 16:10881–10890Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Melanie Sellmeier
    • 1
  • Birgit Weinhold
    • 1
  • Anja Münster-Kühnel
    • 1
  1. 1.Institute for Cellular Chemistry, Hannover Medical School (MHH)HannoverGermany

Personalised recommendations