Beta-1,4 N-Acetylgalactosaminyltransferase 1,2 (B4GALNT1,2)

  • Koichi Furukawa
  • Keiko Furukawa
  • Yuhsuke Ohmi
  • Yuki Ohkawa
  • Yoshio Yamauchi
  • Noboru Hashimoto
  • Orie Tajima
Reference work entry


UDP-GalNAc: GM3 beta-1,4 N-acetylgalactosaminyltransferase (B4GALNT1) catalyzes the transfer of N-acetylgalactosamine from UDP-GalNAc to ganglioside GM3 (Nagata et al. 1992) as shown in Fig. 39.1. The product is GM2. However, this gene product could synthesize not only GM2 but also GD2 and asialo-GM2 (GA2) (Yamashiro et al. 1995) as previously predicted (Pohlentz et al. 1988). These structures are molecules locating at the starting point for the synthesis of mature gangliosides enriched in the nervous tissues such as brain and peripheral nerve tissues. Thus, these complex gangliosides were all deleted in the knockout mice of B4GALNT1 (Takamiya et al. 1996). In addition to the first cDNA clones responsible for the synthesis of GM2 and GD2, a similar enzyme with high homology was identified (Smith and Lowe 1994; Montiel et al. 2003). Thereafter, GM2/GD2/GA2 gene was designated B4GALNT1, and the latter has been called as B4GALNT2. Structures of acceptor substrates are very similar to each other (GM3 vs. sialylparagloboside), but the substrate specificities of them are clearly distinct, i.e., B4GALNT2 catalyzes the synthesis of Sda antigen (or Cad antigen), GalNAcβ1,4(α2,3NeuAc)Galβ1,4GlcNAc-R (Yamashiro et al. 1995). Following the cloning of mouse cDNA (Smith and Lowe 1994), human cDNA was isolated (Montiel et al. 2003). In human cDNAs of B4GALNT2, presence of two isoforms with different length in N-terminus (cytoplasmic region) was reported, while the implication of them has not been clarified (Montiel et al. 2003).


Seminiferous Tubule Hypoglossal Nerve Acceptor Substrate Small Cell Lung Cancer Cell Peripheral Nerve Tissue 


  1. Becker JC, Pancook JD, Gillies SD, Furukawa K, Reisfeld RA (1996a) T cell-mediated eradication of murine metastatic melanoma induced by targeted interleukin 2 therapy. J Exp Med 183:2361–2366PubMedCrossRefGoogle Scholar
  2. Becker JC, Varki N, Gillies SD, Furukawa K, Reisfeld RA (1996b) Long-lived and transferable tumor immunity in mice following targeted interleukin 2 therapy. J Clin Invest 98:2801–2804PubMedCentralPubMedCrossRefGoogle Scholar
  3. Blanchard D, Cartron JP, Fournet B, Montreuil J, van Halbeek H, Vliegenthart JF (1983) Primary structure of the oligosaccharide determinant of blood group Cad specificity. J Biol Chem 258:7691–7695PubMedGoogle Scholar
  4. Bowes T, Wagner ER, Boffey J, Nicholl D, Cochrane L, Benboubetra M, Conner J, Furukawa K, Furukawa K, Willison HJ (2002) Tolerance to self gangliosides is the major factor restricting the antibody response to lipopolysaccharide core oligosaccharides in Campylobacter jejuni strains associated with Guillain-Barré syndrome. Infect Immun 70:5008–5018PubMedCentralPubMedCrossRefGoogle Scholar
  5. Cheung NK, Saarinen UM, Neely JE, Landmeier B, Donovan D, Coccia PF (1985) Monoclonal antibodies to a glycolipid antigen on human neuroblastoma cells. Cancer Res 45:2642–2649PubMedGoogle Scholar
  6. Daniotti JL, Rosales Fritz VM, Martina JA, Furukawa K, Maccioni HJ (1997) Expression of beta 1-4 N-acetylgalactosaminyltransferase gene in the developing rat brain and retina: mRNA, protein immunoreactivity and enzyme activity. Neurochem Int 31:11–19PubMedCrossRefGoogle Scholar
  7. Dohi T, Kawamura YI (2008) Incomplete synthesis of the Sda/Cad blood group carbohydrate in gastrointestinal cancer. Biochim Biophys Acta 1780:467–471PubMedCrossRefGoogle Scholar
  8. Dohi T, Yuyama Y, Natori Y, Smith PL, Lowe JB, Oshima M (1996) Detection of N-acetylgalactosaminyltransferase mRNA which determines expression of Sda blood group carbohydrate structure in human gastrointestinal mucosa and cancer. Int J Cancer 67:626–631PubMedCrossRefGoogle Scholar
  9. Fukuda M, Horibe K, Furukawa K (1998) Enhancement of in vitro and in vivo anti-tumor activity of anti-GD2 monoclonal antibody 220-51 against human neuroblastoma by granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor. Int J Mol Med 2:471–475PubMedGoogle Scholar
  10. Fukumoto S, Yamamoto A, Hasegawa T, Abe K, Takamiya K, Okada M, Min ZJ, Furukawa K, Miyazaki H, Tsuji Y, Goto G, Suzuki M, Shiku H, Furukawa K (1997) Genetic remodeling of gangliosides resulted in the enhanced reactions to the foreign substances in skin. Glycobiology 7:1111–1120PubMedCrossRefGoogle Scholar
  11. Furukawa K, Akagi T, Nagata Y, Yamada Y, Shimotohno K, Cheung NK, Shiku H, Furukawa K (1993) GD2 ganglioside on human T-lymphotropic virus type I-infected T cells: possible activation of beta-1,4-N-acetylgalactosaminyltransferase gene by p40tax. Proc Natl Acad Sci USA 90:1972–1976PubMedCrossRefGoogle Scholar
  12. Furukawa K, Hamamura K, Ohkawa Y, Ohmi Y, Furukawa K (2012) Disialyl gangliosides enhance tumor phenotypes with differential modalities. Glycoconj J 29:579–584PubMedCrossRefGoogle Scholar
  13. Furukawa K, Soejima H, Niikawa N, Shiku H (1996) Genomic organization and chromosomal assignment of the human beta1, 4-N-acetylgalactosaminyltransferase gene. Identification of multiple transcription units. J Biol Chem 271:20836–20844PubMedCrossRefGoogle Scholar
  14. Furukawa K, Tsuchida A, Furukawa K (2007) Biosynthesis of glycolipids. In: Kamerling JP, Boons GJ, Lee YC, Suzuki A, Taniguchi N, Voragen AGJ (eds) Comprehensive glycoscience; chemistry to systems biology, vol. 3. Elsevier, Oxford, pp 105–114CrossRefGoogle Scholar
  15. Haraguchi M, Yamashiro S, Furukawa K, Takamiya K, Shiku H, Furukawa K (1995) The effects of the site-directed removal of N-glycosylation sites from beta-1,4-N-acetylgalactosaminyltransferase on its function. Biochem J 312:273–280PubMedGoogle Scholar
  16. Hashimoto Y, Sekine M, Iwasaki K, Suzuki A (1993) Purification and characterization of UDP-N-acetylgalactosamine GM3/GD3 N-acetylgalactosaminyltransferase from mouse liver. J Biol Chem 268:25857–25864PubMedGoogle Scholar
  17. Hidari JK, Ichikawa S, Furukawa K, Yamasaki M, Hirabayashi Y (1994) beta 1-4 N-acetylgalactosaminyltransferase can synthesize both asialoglycosphingolipid GM2 and glycosphingolipid GM2 in vitro and in vivo: isolation and characterization of a beta 1-4 N-acetylgalactosaminyltransferase cDNA clone from rat ascites hepatoma cell line AH7974F. Biochem J 303:957–965PubMedGoogle Scholar
  18. Hyuga S, Yamagata S, Takatsu Y, Hyuga M, Nakanishi H, Furukawa K, Yamagata T (1999) Suppression by ganglioside GD1A of migration capability, adhesion to vitronectin and metastatic potential of highly metastatic FBJ-LL cells. Int J Cancer 83:685–691PubMedCrossRefGoogle Scholar
  19. Ikarashi K, Fujiwara H, Yamazaki Y, Goto J, Kaneko K, Kato H, Fujii S, Sasaki H, Fukumoto S, Furukawa K, Waki H, Furukawa K (2011) Impaired hippocampal long-term potentiation and failure of learning in β1,4-N-acetylgalacto-saminyltransferase gene transgenic mice. Glycobiology 21:1373–1381PubMedCrossRefGoogle Scholar
  20. Inoue M, Fujii Y, Furukawa K, Okada M, Okumura K, Hayakawa T, Furukawa K, Sugiura Y (2002) Refractory skin injury in complex knock-out mice expressing only the GM3 ganglioside. J Biol Chem 277:29881–29888PubMedCrossRefGoogle Scholar
  21. Jaskiewicz E, Zhu G, Bassi R, Darling DS, Young WW Jr (1996) Beta1,4-N-acetylgalactosaminyltransferase (GM2 synthase) is released from Golgi membranes as a neuraminidase-sensitive, disulfide-bonded dimer by a cathepsin D-like protease. J Biol Chem 271:26395–26403PubMedCrossRefGoogle Scholar
  22. Kawamura YI, Toyota M, Kawashima R, Hagiwara T, Suzuki H, Imai K, Shinomura Y, Tokino T, Kannagi R, Dohi T (2008) DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. Gastroenterology 135:142–151.e3. doi:10.1053/j.gastro.2008.03.031PubMedCrossRefGoogle Scholar
  23. Kittaka D, Itoh M, Ohmi Y, Kondo Y, Fukumoto S, Urano T, Tajima O, Furukawa K, Furukawa K (2008) Impaired hypoglossal nerve regeneration in mutant mice lacking complex gangliosides: down-regulation of neurotrophic factors and receptors as possible mechanisms. Glycobiology 18:509–516. doi:10.1093/glycob/cwn032PubMedCrossRefGoogle Scholar
  24. Kushner BH, Kramer K, Modak S, Cheung NK (2011) Successful multifold dose escalation of anti-GD2 monoclonal antibody 3F8 in patients with neuroblastoma: a phase I study. J Clin Oncol 29:1168–1174PubMedCrossRefGoogle Scholar
  25. Lode HN, Schmidt M, Seidel D, Huebener N, Brackrock D, Bleeke M, Reker D, Brandt S, Mueller HP, Helm C, Siebert N (2013) Vaccination with anti-idiotype antibody ganglidiomab mediates a GD2-specific anti-neuroblastoma immune response. Cancer Immunol ImmunotherGoogle Scholar
  26. Malagolini N, Dall’Olio F, Di Stefano G, Minni F, Marrano D, Serafini-Cessi F (1989) Expression of UDP-GalNAc: NeuAc alpha 2,3Gal beta-R beta 1,4(GalNAc to Gal) N-acetylgalactosaminyltransferase involved in the synthesis of Sda antigen in human large intestine and colorectal carcinomas. Cancer Res 49:6466–6470PubMedGoogle Scholar
  27. Montiel MD, Krzewinski-Recchi MA, Delannoy P, Harduin-Lepers A (2003) Molecular cloning, gene organization and expression of the human UDP-GalNAc: Neu5Acalpha2-3Galbeta-R beta1,4-N-acetylgalactosaminyltransferase responsible for the biosynthesis of the blood group Sda/Cad antigen: evidence for an unusual extended cytoplasmic domain. Biochem J 373:369–379PubMedCrossRefGoogle Scholar
  28. Morton JA, Pickles MM, Terry AM (1970) The Sda blood group antigen in tissues and body fluids. Vox Sang 19:472–482PubMedCrossRefGoogle Scholar
  29. Nagafuku M, Okuyama K, Onimaru Y, Suzuki A, Odagiri Y, Yamashita T, Iwasaki K, Fujiwara M, Takayanagi M, Ohno I, Inokuchi J (2012) CD4 and CD8 T cells require different membrane gangliosides for activation. Proc Natl Acad Sci USA 109:E336–E342. doi:10.1073/pnas.1114965109PubMedCrossRefGoogle Scholar
  30. Nagata Y, Yamashiro S, Yodoi J, Lloyd KO, Shiku H, Furukawa K (1992) Expression cloning of beta 1,4 N-acetylgalactosaminyltransferase cDNAs that determine the expression of GM2 and GD2 gangliosides. J Biol Chem 267:12082–12089PubMedGoogle Scholar
  31. Ohmi Y, Tajima O, Ohkawa Y, Mori A, Sugiura Y, Furukawa K, Furukawa K (2009) Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues. Proc Natl Acad Sci USA 106:22405–22410PubMedCrossRefGoogle Scholar
  32. Oikawa N, Yamaguchi H, Ogino K, Taki T, Yuyama K, Yamamoto N, Shin RW, Furukawa K, Yanagisawa K (2009) Gangliosides determine the amyloid pathology of Alzheimer’s disease. Neuroreport 20:1043–1046PubMedGoogle Scholar
  33. Pohlentz G, Klein D, Schwarzmann G, Schmitz D, Sandhoff K (1988) Both GA2, GM2, and GD2 synthases and GM1b, GD1a, and GT1b synthases are single enzymes in Golgi vesicles from rat liver. Proc Natl Acad Sci USA 85:7044–7048PubMedCrossRefGoogle Scholar
  34. Ruan S, Raj BK, Furukawa K, Lloyd KO (1995) Analysis of melanoma cells stably transfected with beta 1,4GalNAc transferase (GM2/GD2 synthase) cDNA: relative glycosyltransferase levels play a dominant role in determining ganglioside expression. Arch Biochem Biophys 323:11–18PubMedCrossRefGoogle Scholar
  35. Sen G, Chakraborty M, Foon KA, Reisfeld RA, Bhattacharya-Chatterjee M (1997) Preclinical evaluation in nonhuman primates of murine monoclonal anti-idiotype antibody that mimics the disialoganglioside GD2. Clin Cancer Res 3:1969–1976PubMedGoogle Scholar
  36. Sheikh KA, Sun J, Liu Y, Kawai H, Crawford TO, Proia RL, Griffin JW, Schnaar RL (1999) Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc Natl Acad Sci USA 96:7532–7537PubMedCrossRefGoogle Scholar
  37. Shibuya H, Hamamura K, Hotta H, Matsumoto Y, Nishida Y, Hattori H, Furukawa K, Ueda M, Furukawa K (2012) Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. Cancer Sci 103:1656–1664PubMedCrossRefGoogle Scholar
  38. Smith PL, Lowe JB (1994) Molecular cloning of a murine N-acetylgalactosamine transferase cDNA that determines expression of the T lymphocyte-specific CT oligosaccharide differentiation antigen. J Biol Chem 269:15162–15171PubMedGoogle Scholar
  39. Soh CP, Morgan WT, Watkins WM, Donald AS (1980) The relationship between the N-acetylgalactosamine content and the blood group Sda activity of Tamm and Horsfall urinary glycoprotein. Biochem Biophys Res Commun 93:1132–1139PubMedCrossRefGoogle Scholar
  40. Soh CP, Donald AS, Feeney J, Morgan WT, Watkins WM (1989) Enzymic synthesis, chemical characterisation and Sda activity of GalNAc beta 1-4[NeuAc alpha 2-3]Gal beta 1-4GlcNAc and GalNAc beta 1-4[NeuAc alpha 2-3]Gal beta 1-4Glc. Glycoconj J 6:319–332PubMedCrossRefGoogle Scholar
  41. Sugiura Y, Furukawa K, Tajima O, Mii S, Honda T, Furukawa K (2005) Sensory nerve-dominant nerve degeneration and remodeling in the mutant mice lacking complex gangliosides. Neuroscience 135:1167–1178PubMedCrossRefGoogle Scholar
  42. Tai T, Cahan LD, Paulson JC, Saxton RE, Irie RF (1984) Human monoclonal antibody against ganglioside GD2: use in development of enzyme-linked immunosorbent assay for the monitoring of anti-GD2 in cancer patients. J Natl Cancer Inst 73:627–633PubMedGoogle Scholar
  43. Takamiya K, Yamamoto A, Yamashiro S, Furukawa K, Haraguchi M, Okada M, Ikeda T, Shiku H, Furukawa K (1995) T cell receptor-mediated stimulation of mouse thymocytes induces up-regulation of the GM2/GD2 synthase gene. FEBS Lett 358:79–83PubMedCrossRefGoogle Scholar
  44. Takamiya K, Yamamoto A, Furukawa K, Yamashiro S, Shin M, Okada M, Fukumoto S, Haraguchi M, Takeda N, Fujimura K, Sakae M, Kishikawa M, Shiku H, Furukawa K, Aizawa S (1996) Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc Natl Acad Sci USA 93:10662–10667PubMedCrossRefGoogle Scholar
  45. Takamiya K, Yamamoto A, Furukawa K, Zhao J, Fukumoto S, Yamashiro S, Okada M, Haraguchi M, Shin M, Kishikawa M, Shiku H, Aizawa S, Furukawa K (1998) Complex gangliosides are essential in spermatogenesis of mice: possible roles in the transport of testosterone. Proc Natl Acad Sci USA 95:12147–12152PubMedCrossRefGoogle Scholar
  46. Tsurifune T, Ito T, Li XJ, Yamashiro S, Okada M, Kanematsu T, Shiku H, Furukawa K (2000) Alteration of tumor phenotypes of B16 melanoma after genetic remodeling of the ganglioside profile. Int J Oncol 17:159–165PubMedGoogle Scholar
  47. Watanabe T, Pukel CS, Takeyama H, Lloyd KO, Shiku H, Li LT, Travassos LR, Oettgen HF, Old LJ (1982) Human melanoma antigen AH is an autoantigenic ganglioside related to GD2. J Exp Med 156:1884–1889PubMedCrossRefGoogle Scholar
  48. Yamamoto A, Yamashiro S, Takamiya K, Atsuta M, Shiku H, Furukawa K (1995) Diverse expression of mRNA of b1,4-N-acetylgalactosaminyltransferase gene in the adult mouse brain. J Neurochem 65:2417–2424PubMedCrossRefGoogle Scholar
  49. Yamamoto A, Haraguchi M, Yamashiro S, Fukumoto S, Furukawa K, Takamiya K, Atsuta M, Shiku H, Furukawa K (1996) Heterogeneity in the expression pattern of two ganglioside synthase genes during mouse brain development. J Neurochem 66:26–34PubMedCrossRefGoogle Scholar
  50. Yamashiro S, Ruan S, Furukawa K, Tai T, Lloyd KO, Shiku H, Furukawa K (1993) Genetic and enzymatic basis for the differential expression of GM2 and GD2 gangliosides in human cancer cell lines. Cancer Res 53:5395–5400PubMedGoogle Scholar
  51. Yamashiro S, Haraguchi M, Furukawa K, Takamiya K, Yamamoto A, Nagata Y, Lloyd KO, Shiku H, Furukawa K (1995) Substrate specificity of beta 1,4-N-acetylgalactosaminyltransferase in vitro and in cDNA-transfected cells. GM2/GD2 synthase efficiently generates asialo-GM2 in certain cells. J Biol Chem 270:6149–6155PubMedCrossRefGoogle Scholar
  52. Yanagisawa K, Odaka A, Suzuki N, Ihara Y (1995) GM1 ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer’s disease. Nat Med 1:1062–1066PubMedCrossRefGoogle Scholar
  53. Yoshida S, Fukumoto S, Kawaguchi H, Sato S, Ueda D, Furukawa K (2001) Ganglioside GD2 in small cell lung cancer cell lines: enhancement of cell proliferation and mediation of apoptosis. Cancer Res 61:4244–4252PubMedGoogle Scholar
  54. Yoshimura A, Takamiya K, Kato I, Nakayama E, Shiku H, Furukawa K (1994) GD2 ganglioside-specific monoclonal antibody reacts with murine cytotoxic T lymphocytes reactive with FBL-3 N erythroleukaemia. Scand J Immunol 40:557–563PubMedCrossRefGoogle Scholar
  55. Yuki N, Susuki K, Koga M, Nishimoto Y, Odaka M, Hirata K, Taguchi K, Miyatake T, Furukawa K, Kobata T, Yamada M (2004) Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes Guillain-Barre syndrome. Proc Natl Acad Sci USA 101:11404–11409PubMedCrossRefGoogle Scholar
  56. Yuyama Y, Dohi T, Morita H, Furukawa K, Oshima M (1995) Enhanced expression of GM2/GD2 synthase mRNA in human gastrointestinal cancer. Cancer 75:1273–1280PubMedCrossRefGoogle Scholar
  57. Zhao J, Furukawa K, Fukumoto S, Okada M, Furugen R, Miyazaki H, Takamiya K, Aizawa S, Shiku H, Matsuyama T, Furukawa K (1999) Attenuation of interleukin 2 signal in the spleen cells of complex ganglioside-lacking mice. J Biol Chem 274:13744–13747PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  • Koichi Furukawa
    • 1
  • Keiko Furukawa
    • 2
  • Yuhsuke Ohmi
    • 1
  • Yuki Ohkawa
    • 1
  • Yoshio Yamauchi
    • 1
  • Noboru Hashimoto
    • 1
  • Orie Tajima
    • 2
  1. 1.Department of Biochemistry IINagoya University Graduate School of MedicineShowa-kuJapan
  2. 2.Department of Biomedical SciencesChubu University College of Life and Health SciencesKasugaiJapan

Personalised recommendations