Beta-1,3-Glucuronyltransferase 1 (Glucuronosyltransferase P); Beta-1,3-Glucuronyltransferase 2 (B3GAT1,2)

  • Yasuhiko Kizuka
  • Shogo Oka
Reference work entry


The human natural killer-1 (HNK-1) carbohydrate epitope, composed of a unique acidic trisaccharide HSO3-3GlcAβ1-3Galβ1-4GlcNAc-, is highly expressed in the nervous system. The HNK-1 epitope is found in N-linked and O-mannose-linked glycans of glycoproteins and also in some glycolipids (Chou et al. 1986; Kouno et al. 2011; Yuen et al. 1997). Intriguingly, limited glycoproteins are modified with the HNK-1 epitope such as the immunoglobulin-superfamily cell adhesion molecules (NCAM, L1, MAG, P0, etc.), extracellular matrix proteins (tenascin-R, phosphacan, etc.), and a glutamate receptor subunit (GluA2) (Kizuka and Oka 2012), suggesting that the HNK-1 glycan is expressed in a tightly regulated manner in the neural cells. As for physiological function, HNK-1 glycan is required for memory and learning, revealed by studies using enzyme-deficient mice (Senn et al. 2002; Yamamoto et al. 2002; Yoshihara et al. 2009). The unique structure of the HNK-1 glycan is attributed to a sulfated GlcA residue that is rarely seen in other N-linked and O-mannose-linked glycans, and key enzymes for the biosynthesis are two glucuronyltransferases, GlcAT-P and GlcAT-S (B3GAT1 and 2, respectively), and a sulfotransferase, HNK-1ST (see  Chap. 92, “Carbohydrate Sulfotransferase 10 (CHST10)”). In this chapter, enzymatic features of the two glucuronyltransferases are further described, which should help us to understand the functions and expression mechanisms of the HNK-1 glycan.


Glycan Structure Acceptor Substrate Glutamate Receptor Subunit Trichloroacetic Acid Solution Glucuronyltransferase Activity 
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  1. Abo T, Balch CM (1981) A differentiation antigen of human NK and K cells identified by a monoclonal antibody (HNK-1). J Immunol 127:1024–1029PubMedGoogle Scholar
  2. Allory Y, Commo F, Boccon-Gibod L, Sibony M, Callard P, Ronco P, Debiec H (2006) Sulfated HNK-1 epitope in developing and mature kidney: a new marker for thin ascending loop of Henle and tubular injury in acute tubular necrosis. J Histochem Cytochem 54:575–584PubMedCrossRefGoogle Scholar
  3. Ariga T et al (1987) Characterization of sulfated glucuronic acid containing glycolipids reacting with IgM M-proteins in patients with neuropathy. J Biol Chem 262:848–853PubMedGoogle Scholar
  4. Bakker H, Friedmann I, Oka S, Kawasaki T, Nifant’ev N, Schachner M, Mantei N (1997) Expression cloning of a cDNA encoding a sulfotransferase involved in the biosynthesis of the HNK-1 carbohydrate epitope. J Biol Chem 272:29942–29946PubMedCrossRefGoogle Scholar
  5. Bronner-Fraser M (1986) Analysis of the early stages of trunk neural crest migration in avian embryos using monoclonal antibody HNK-1. Dev Biol 115:44–55PubMedCrossRefGoogle Scholar
  6. Chou DK, Flores S, Jungalwala FB (1991) Expression and regulation of UDP-glucuronate: neolactotetraosylceramide glucuronyltransferase in the nervous system. J Biol Chem 266:17941–17947PubMedGoogle Scholar
  7. Chou DK, Ilyas AA, Evans JE, Costello C, Quarles RH, Jungalwala FB (1986) Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy. J Biol Chem 261:11717–11725PubMedGoogle Scholar
  8. Das KK, Basu M, Basu S, Chou DK, Jungalwala FB (1991) Biosynthesis in vitro of GlcA beta 1-3nLcOse4Cer by a novel glucuronyltransferase (GlcAT-1) from embryonic chicken brain. J Biol Chem 266:5238–5243PubMedGoogle Scholar
  9. Debanne D (1996) Associative synaptic plasticity in hippocampus and visual cortex: cellular mechanisms and functional implications. Rev Neurosci 7:29–46PubMedCrossRefGoogle Scholar
  10. Ilyas AA, Quarles RH, MacIntosh TD, Dobersen MJ, Trapp BD, Dalakas MC, Brady RO (1984) IgM in a human neuropathy related to paraproteinemia binds to a carbohydrate determinant in the myelin-associated glycoprotein and to a ganglioside. Proc Natl Acad Sci USA 81:1225–1229PubMedCentralPubMedCrossRefGoogle Scholar
  11. Isaac JT, Ashby MC, McBain CJ (2007) The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 54:859–871PubMedCrossRefGoogle Scholar
  12. Jeffries AR, Mungall AJ, Dawson E, Halls K, Langford CF, Murray RM, Dunham I, Powell JF (2003) Beta-1,3-glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation. Mol Psychiatry 8:654–663PubMedCrossRefGoogle Scholar
  13. Kahler AK et al (2011) Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area. Biol Psychiatry 69:90–96PubMedCrossRefGoogle Scholar
  14. Kakuda S, Oka S, Kawasaki T (2004a) Purification and characterization of two recombinant human glucuronyltransferases involved in the biosynthesis of HNK-1 carbohydrate in Escherichia coli. Protein Expr Purif 35:111–119PubMedCrossRefGoogle Scholar
  15. Kakuda S, Sato Y, Tonoyama Y, Oka S, Kawasaki T (2005) Different acceptor specificities of two glucuronyltransferases involved in the biosynthesis of HNK-1 carbohydrate. Glycobiology 15:203–210PubMedCrossRefGoogle Scholar
  16. Kakuda S, Shiba T, Ishiguro M, Tagawa H, Oka S, Kajihara Y, Kawasaki T, Wakatsuki S, Kato R (2004b) Structural basis for acceptor substrate recognition of a human glucuronyltransferase, GlcAT-P, an enzyme critical in the biosynthesis of the carbohydrate epitope HNK-1. J Biol Chem 279:22693–22703PubMedCrossRefGoogle Scholar
  17. Kawashima C, Terayama K, Ii M, Oka S, Kawasaki T (1992) Characterization of a glucuronyltransferase: neolactotetraosylceramide glucuronyltransferase from rat brain. Glycoconj J 9:307–314PubMedCrossRefGoogle Scholar
  18. Kitagawa H, Tone Y, Tamura J, Neumann KW, Ogawa T, Oka S, Kawasaki T, Sugahara K (1998) Molecular cloning and expression of glucuronyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans. J Biol Chem 273:6615–6618PubMedCrossRefGoogle Scholar
  19. Kizuka Y, Kobayashi K, Kakuda S, Nakajima Y, Itoh S, Kawasaki N, Oka S (2008) Laminin-1 is a novel carrier glycoprotein for the nonsulfated HNK-1 epitope in mouse kidney. Glycobiology 18:331–338PubMedCrossRefGoogle Scholar
  20. Kizuka Y, Matsui T, Takematsu H, Kozutsumi Y, Kawasaki T, Oka S (2006) Physical and functional association of glucuronyltransferases and sulfotransferase involved in HNK-1 biosynthesis. J Biol Chem 281:13644–13651PubMedCrossRefGoogle Scholar
  21. Kizuka Y, Oka S (2012) Regulated expression and neural functions of human natural killer-1 (HNK-1) carbohydrate. Cell Mol Life Sci 69:4135PubMedCrossRefGoogle Scholar
  22. Kizuka Y, Tonoyama Y, Oka S (2009) Distinct transport and intracellular activities of two GlcAT-P isoforms. J Biol Chem 284:9247–9256PubMedCrossRefGoogle Scholar
  23. Kouno T, Kizuka Y, Nakagawa N, Yoshihara T, Asano M, Oka S (2011) Specific enzyme complex of beta-1,4-galactosyltransferase-II and glucuronyltransferase-P facilitates biosynthesis of N-linked human natural killer-1 (HNK-1) carbohydrate. J Biol Chem 286:31337–31346PubMedCrossRefGoogle Scholar
  24. Kruse J, Mailhammer R, Wernecke H, Faissner A, Sommer I, Goridis C, Schachner M (1984) Neural cell adhesion molecules and myelin-associated glycoprotein share a common carbohydrate moiety recognized by monoclonal antibodies L2 and HNK-1. Nature 311:153–155PubMedCrossRefGoogle Scholar
  25. Morita I, Kakuda S, Takeuchi Y, Itoh S, Kawasaki N, Kizuka Y, Kawasaki T, Oka S (2009a) HNK-1 glyco-epitope regulates the stability of the glutamate receptor subunit GluR2 on the neuronal cell surface. J Biol Chem 284:30209–30217PubMedCrossRefGoogle Scholar
  26. Morita I, Kakuda S, Takeuchi Y, Kawasaki T, Oka S (2009b) HNK-1 (human natural killer-1) glyco-epitope is essential for normal spine morphogenesis in developing hippocampal neurons. Neuroscience 164:1685–1694PubMedCrossRefGoogle Scholar
  27. Obata K, Tanaka H (1988) Molecular differentiation of the otic vesicle and neural tube in the chick embryo demonstrated by monoclonal antibodies. Neurosci Res 6:131–142PubMedCrossRefGoogle Scholar
  28. Oka S, Terayama K, Kawashima C, Kawasaki T (1992) A novel glucuronyltransferase in nervous system presumably associated with the biosynthesis of HNK-1 carbohydrate epitope on glycoproteins. J Biol Chem 267:22711–22714PubMedGoogle Scholar
  29. Ong E, Suzuki M, Belot F, Yeh JC, Franceschini I, Angata K, Hindsgaul O, Fukuda M (2002) Biosynthesis of HNK-1 glycans on O-linked oligosaccharides attached to the neural cell adhesion molecule (NCAM): the requirement for core 2 beta 1,6-N-acetylglucosaminyltransferase and the muscle-specific domain in NCAM. J Biol Chem 277:18182–18190PubMedCrossRefGoogle Scholar
  30. Ong E, Yeh JC, Ding Y, Hindsgaul O, Fukuda M (1998) Expression cloning of a human sulfotransferase that directs the synthesis of the HNK-1 glycan on the neural cell adhesion molecule and glycolipids. J Biol Chem 273:5190–5195PubMedCrossRefGoogle Scholar
  31. Saglietti L et al (2007) Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron 54:461–477PubMedCrossRefGoogle Scholar
  32. Schwarting GA, Jungalwala FB, Chou DK, Boyer AM, Yamamoto M (1987) Sulfated glucuronic acid-containing glycoconjugates are temporally and spatially regulated antigens in the developing mammalian nervous system. Dev Biol 120:65–76PubMedCrossRefGoogle Scholar
  33. Segal M (2005) Dendritic spines and long-term plasticity. Nat Rev Neurosci 6:277–284PubMedCrossRefGoogle Scholar
  34. Seiki T, Oka S, Terayama K, Imiya K, Kawasaki T (1999) Molecular cloning and expression of a second glucuronyltransferase involved in the biosynthesis of the HNK-1 carbohydrate epitope. Biochem Biophys Res Commun 255:182–187PubMedCrossRefGoogle Scholar
  35. Senn C, Kutsche M, Saghatelyan A, Bosl MR, Lohler J, Bartsch U, Morellini F, Schachner M (2002) Mice deficient for the HNK-1 sulfotransferase show alterations in synaptic efficacy and spatial learning and memory. Mol Cell Neurosci 20:712–729PubMedCrossRefGoogle Scholar
  36. Shiba T, Kakuda S, Ishiguro M, Morita I, Oka S, Kawasaki T, Wakatsuki S, Kato R (2006) Crystal structure of GlcAT-S, a human glucuronyltransferase, involved in the biosynthesis of the HNK-1 carbohydrate epitope. Proteins 65:499–508PubMedCrossRefGoogle Scholar
  37. Shimoda Y, Tajima Y, Nagase T, Harii K, Osumi N, Sanai Y (1999) Cloning and expression of a novel galactoside beta1, 3-glucuronyltransferase involved in the biosynthesis of HNK-1 epitope. J Biol Chem 274:17115–17122PubMedCrossRefGoogle Scholar
  38. Tagawa H et al (2005) A non-sulfated form of the HNK-1 carbohydrate is expressed in mouse kidney. J Biol Chem 280:23876–23883PubMedCrossRefGoogle Scholar
  39. Tang NE, Luyten GP, Mooy CM, Naus NC, de Jong PT, Luider TM (1996) HNK-1 antigens on uveal and cutaneous melanoma cell lines. Melanoma Res 6:411–418PubMedCrossRefGoogle Scholar
  40. Terayama K, Oka S, Seiki T, Miki Y, Nakamura A, Kozutsumi Y, Takio K, Kawasaki T (1997) Cloning and functional expression of a novel glucuronyltransferase involved in the biosynthesis of the carbohydrate epitope HNK-1. Proc Natl Acad Sci U S A 94:6093–6098PubMedCentralPubMedCrossRefGoogle Scholar
  41. Terayama K, Seiki T, Nakamura A, Matsumori K, Ohta S, Oka S, Sugita M, Kawasaki T (1998) Purification and characterization of a glucuronyltransferase involved in the biosynthesis of the HNK-1 epitope on glycoproteins from rat brain. J Biol Chem 273:30295–30300PubMedCrossRefGoogle Scholar
  42. Thies A, Schachner M, Berger J, Moll I, Schulze HJ, Brunner G, Schumacher U (2004) The developmentally regulated neural crest-associated glycotope HNK-1 predicts metastasis in cutaneous malignant melanoma. J Pathol 203:933–939PubMedCrossRefGoogle Scholar
  43. Tucker GC, Aoyama H, Lipinski M, Tursz T, Thiery JP (1984) Identical reactivity of monoclonal antibodies HNK-1 and NC-1: conservation in vertebrates on cells derived from the neural primordium and on some leukocytes. Cell Differ 14:223–230PubMedCrossRefGoogle Scholar
  44. Uemura S, Yoshida S, Shishido F, Inokuchi J (2009) The cytoplasmic tail of GM3 synthase defines its subcellular localization, stability, and in vivo activity. Mol Biol Cell 20:3088–3100PubMedCentralPubMedCrossRefGoogle Scholar
  45. Yamamoto S et al (2002) Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning. J Biol Chem 277:27227–27231PubMedCrossRefGoogle Scholar
  46. Yoshihara T, Sugihara K, Kizuka Y, Oka S, Asano M (2009) Learning/memory impairment and reduced expression of the HNK-1 carbohydrate in beta4-galactosyltransferase-II-deficient mice. J Biol Chem 284:12550–12561PubMedCrossRefGoogle Scholar
  47. Youakim A, Dubois DH, Shur BD (1994) Localization of the long form of beta-1,4-galactosyltransferase to the plasma membrane and Golgi complex of 3 T3 and F9 cells by immunofluorescence confocal microscopy. Proc Natl Acad Sci U S A 91:10913–10917PubMedCentralPubMedCrossRefGoogle Scholar
  48. Yuen CT, Chai W, Loveless RW, Lawson AM, Margolis RU, Feizi T (1997) Brain contains HNK-1 immunoreactive O-glycans of the sulfoglucuronyl lactosamine series that terminate in 2-linked or 2,6-linked hexose (mannose). J Biol Chem 272:8924–8931PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Department of Biological Chemistry, Human Health Sciences, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Disease Glycomics Team, RIKEN-Max Planck Joint Research CenterRIKENWakoJapan

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