N-Deacetylase/N-Sulfotransferase (Heparan Glucosaminyl) 1 (NDST1)

  • Kay Grobe
Reference work entry


Heparan sulfate (HS) is expressed on virtually all cells of vertebrate and invertebrate developing embryos and adult tissues as part of HS proteoglycans (HSPGs). The HSPGs perlecan, agrin, and collagen XVIII are found in basement membranes, while HSPGs belonging to the syndecan and glypican families are cell surface bound. Many growth factors, morphogens, chemokines, and cytokines bind to HS, and HSPGs are thought to act as coreceptors for these molecules. In addition, HSPGs play important roles in cell-matrix adhesion, lipoprotein metabolism, virus and parasite infection, and protease/protease inhibitor binding and activity regulation (Kjellén and Lindahl 1991). This makes regulated HS biosynthesis essential for unimpaired embryonic development as well as for adult homeostasis.


Heparan Sulfate Heparan Sulfate Chain Treacher Collins Syndrome Sulfotransferase Activity Heparan Sulfate Binding 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abramsson A, Kurup S, Busse M, Yamada S, Lindblom P, Schallmeiner E, Stenzel D, Sauvaget D, Ledin J, Ringvall M, Landegren U, Kjellen L, Bondjers G, Li JP, Lindahl U, Spillmann D, Betsholtz C, Gerhardt H (2007) Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev 21:316–331PubMedCrossRefGoogle Scholar
  2. Adhikari N, Basi DL, Townsend D, Rusch M, Mariash A, Mullegama S, Watson A, Larson J, Tan S, Lerman B, Esko JD, Selleck SB, Hall JL (2010) Heparan sulfate Ndst1 regulates vascular smooth muscle cell proliferation, vessel size and vascular remodeling. J Mol Cell Cardiol 49:287–293PubMedCentralPubMedCrossRefGoogle Scholar
  3. Aikawa J, Esko JD (1999) Molecular cloning and expression of a third member of the heparan sulfate/heparin GlcNAc N-deacetylase/N-sulfotransferase family. J Biol Chem 274:2690–2695PubMedCrossRefGoogle Scholar
  4. Aikawa J, Grobe K, Tsujimoto M, Esko JD (2001) Multiple isozymes of heparan sulfate/heparin GlcNAc N-deacetylase/N-sulfotransferase: structure and activity of the fourth member, NDST4. J Biol Chem 276:5876–5882PubMedCrossRefGoogle Scholar
  5. Bame KJ, Reddy RV, Esko JD (1991) Coupling of N-deacetylation and N-sulfation in a chinese hamster ovary cell mutant defective in heparan sulfate N-sulfotransferase. J Biol Chem 266:12461–12468PubMedGoogle Scholar
  6. Carlsson P, Presto J, Spillmann D, Lindahl U, Kjellen L (2008) Heparin/heparan sulfate biosynthesis: processive formation of N-sulfated domains. J Biol Chem 283:20008–20014PubMedCrossRefGoogle Scholar
  7. Crawford BE, Garner OB, Bishop JR, Zhang DY, Bush KT, Nigam SK, Esko JD (2010) Loss of the heparan sulfate sulfotransferase, Ndst1, in mammary epithelial cells selectively blocks lobuloalveolar development in mice. PLoS One 5:e10691. doi:10610.11371/journal.pone.0010691PubMedCentralPubMedCrossRefGoogle Scholar
  8. Duncan G, McCormick C, Tufaro F (2001) The link between heparan sulfate and hereditary bone disease: finding a function for the EXT family of putative tumor suppressor proteins. J Clin Invest 108:511–516PubMedCentralPubMedCrossRefGoogle Scholar
  9. Eriksson I, Sandbäck D, Ek B, Lindahl U, Kjellén L (1994) cDNA cloning and sequencing of mouse mastocytoma glucosaminyl N-deacetylase/N-sulfotransferase, an enzyme involved in the biosynthesis of heparin. J Biol Chem 269:10438–10443PubMedGoogle Scholar
  10. Esko JD, Zhang L (1996) Influence of core protein sequence on glycosaminoglycan assembly. Curr Opin Struct Biol 6:663–670PubMedCrossRefGoogle Scholar
  11. Fan G, Xiao L, Cheng L, Wang X, Sun B, Hu G (2000) Targeted disruption of NDST-1 gene leads to pulmonary hypoplasia and neonatal respiratory distress in mice. FEBS Lett 467:7–11PubMedCrossRefGoogle Scholar
  12. Fuster MM, Wang L, Castagnola J, Sikora L, Reddi K, Lee PH, Radek KA, Schuksz M, Bishop JR, Gallo RL, Sriramarao P, Esko JD (2007) Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis. J Cell Biol 177:539–549PubMedCrossRefGoogle Scholar
  13. Gorokhov A, Perera L, Darden TA, Negishi M, Pedersen LC, Pedersen LG (2000) Heparan sulfate biosynthesis: a theoretical study of the initial sulfation step by N-deacetylase/N-sulfotransferase. Biophys J 79:2909–2917PubMedCentralPubMedCrossRefGoogle Scholar
  14. Grobe K, Inatani M, Pallerla SR, Castagnola J, Yamaguchi Y, Esko JD (2005) Cerebral hypoplasia and craniofacial defects in mice lacking heparan sulfate Ndst1 gene function. Development 132:3777–3786PubMedCrossRefGoogle Scholar
  15. Harfouche R, Hentschel DM, Piecewicz S, Basu S, Print C, Eavarone D, Kiziltepe T, Sasisekharan R, Sengupta S (2009) Glycome and transcriptome regulation of vasculogenesis. Circulation 120:1883–1892PubMedCrossRefGoogle Scholar
  16. Hashimoto Y, Orellana A, Gil G, Hirschberg CB (1992) Molecular cloning and expression of rat liver N-heparan sulfate sulfotransferase. J Biol Chem 267:15744–15750PubMedGoogle Scholar
  17. Holmborn K, Ledin J, Smeds E, Eriksson I, Kusche-Gullberg M, Kjellen L (2004) Heparan sulfate synthesized by mouse embryonic stem cells deficient in NDST1 and NDST2 is 6-O-sulfated but contains no N-sulfate groups. J Biol Chem 279:42355–42358PubMedCrossRefGoogle Scholar
  18. Hu Z, Wang C, Xiao Y, Sheng N, Chen Y, Xu Y, Zhang L, Mo W, Jing N, Hu G (2009) NDST1-dependent heparan sulfate regulates BMP signaling and internalization in lung development. J Cell Sci 122:1145–1154PubMedCrossRefGoogle Scholar
  19. Humphries DE, Sullivan BM, Aleixo MD, Stow JL (1997) Localization of human heparan glucosaminyl N-deacetylase/N-sulphotransferase to the trans-Golgi network. Biochem J 325:351–357PubMedGoogle Scholar
  20. Kakuta Y, Sueyoshi T, Negishi M, Pedersen LC (1999) Crystal structure of the sulfotransferase domain of human heparan sulfate N-deacetylase/N-sulfotransferase 1. J Biol Chem 274:10673–10676PubMedCrossRefGoogle Scholar
  21. Kjellén L, Lindahl U (1991) Proteoglycans: structures and interactions. Annu Rev Biochem 60:443–475PubMedCrossRefGoogle Scholar
  22. Kjellén L, Pettersson I, Unger E, Lindahl U (1992) Two enzymes in one: N-deacetylation and N-sulfation in heparin biosynthesis are catalyzed by the same protein. Adv Exp Med Biol 313:107–111PubMedCrossRefGoogle Scholar
  23. Kobayashi S, Morimoto K, Shimizu T, Takahashi M, Kurosawa H, Shirasawa T (2000) Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus. Biochem Biophys Res Commun 268:860–867PubMedCrossRefGoogle Scholar
  24. Kusche-Gullberg M, Eriksson I, Pikas DS, Kjellén L (1998) Identification and expression in mouse of two heparan sulfate glucosaminyl N-deacetylase/N-sulfotransferase genes. J Biol Chem 273:11902–11907PubMedCrossRefGoogle Scholar
  25. Kusche-Gullberg M, Nybakken K, Perrimon N, Lindahl U (2012) Drosophila heparan sulfate, a novel design. J Biol Chem 287:21950–21956PubMedCrossRefGoogle Scholar
  26. Lin X, Buff EM, Perrimon N, Michelson AM (1999) Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development. Development 126:3715–3723PubMedGoogle Scholar
  27. Lindahl U, Kusche-Gullberg M, Kjellén L (1998) Regulated diversity of heparan sulfate. J Biol Chem 273:24979–24982PubMedCrossRefGoogle Scholar
  28. MacArthur JM, Bishop JR, Stanford KI, Wang L, Bensadoun A, Witztum JL, Esko JD (2007) Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members. J Clin Invest 117:153–164PubMedCentralPubMedCrossRefGoogle Scholar
  29. McCormick C, Duncan G, Goutsos KT, Tufaro F (2000) The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 97:668–673PubMedCentralPubMedCrossRefGoogle Scholar
  30. Orellana A, Hirschberg CB, Wei Z, Swiedler SJ, Ishihara M (1994) Molecular cloning and expression of a glycosaminoglycan N-acetylglucosaminyl N-deacetylase/N-sulfotransferase from a heparin-producing cell line. J Biol Chem 269:2270–2276PubMedGoogle Scholar
  31. Pallerla SR, Lawrence R, Lewejohann L, Pan Y, Fischer T, Schlomann U, Zhang X, Esko JD, Grobe K (2008) Altered heparan sulfate structure in mice with deleted NDST3 gene function. J Biol Chem 283:16885–16894PubMedCrossRefGoogle Scholar
  32. Pallerla SR, Pan Y, Zhang X, Esko JD, Grobe K (2007) Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development. Dev Dyn 236:556–563PubMedCrossRefGoogle Scholar
  33. Pan Y, Carbe C, Powers A, Zhang EE, Esko JD, Grobe K, Feng GS, Zhang X (2008) Bud specific N-sulfation of heparan sulfate regulates Shp2-dependent FGF signaling during lacrimal gland induction. Development 135:301–310PubMedCrossRefGoogle Scholar
  34. Pan Y, Woodbury A, Esko JD, Grobe K, Zhang X (2006) Heparan sulfate biosynthetic gene Ndst1 is required for FGF signaling in early lens development. Development 133:4933–4944PubMedCrossRefGoogle Scholar
  35. Pettersson I, Kusche M, Unger E, Wlad H, Nylund L, Lindahl U, Kjellén L (1991) Biosynthesis of heparin. Purification of a 110-kDa mouse mastocytoma protein required for both glucosaminyl N-deacetylation and N-sulfation. J Biol Chem 266:8044–8049PubMedGoogle Scholar
  36. Pinhal MAS, Smith B, Olson S, Aikawa J, Kimata K, Esko JD (2001) Enzyme interactions in heparan sulfate biosynthesis: uronosyl 5-epimerase and 2-O-sulfotransferase interact in vivo. Proc Natl Acad Sci USA 98:12984–12989PubMedCentralPubMedCrossRefGoogle Scholar
  37. Presto J, Thuveson M, Carlsson P, Busse M, Wilen M, Eriksson I, Kusche-Gullberg M, Kjellen L (2008) Heparan sulfate biosynthesis enzymes EXT1 and EXT2 affect NDST1 expression and heparan sulfate sulfation. Proc Natl Acad Sci USA 105:4751–4756PubMedCentralPubMedCrossRefGoogle Scholar
  38. Qu X, Hertzler K, Pan Y, Grobe K, Robinson ML, Zhang X (2011) Genetic epistasis between heparan sulfate and FGF-Ras signaling controls lens development. Dev Biol 355:12–20PubMedCentralPubMedCrossRefGoogle Scholar
  39. Qu X, Pan Y, Carbe C, Powers A, Grobe K, Zhang X (2012) Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development. Development 139:2730–2739PubMedCrossRefGoogle Scholar
  40. Ringvall M, Ledin J, Holmborn K, Van Kuppevelt T, Ellin F, Eriksson I, Olofsson AM, Kjellén L, Forsberg E (2000) Defective heparan sulfate biosynthesis and neonatal lethality in mice lacking N-deacetylase/N-sulfotransferase-1. J Biol Chem 275:25926–25930PubMedCrossRefGoogle Scholar
  41. Sheng J, Liu R, Xu Y, Liu J (2011) The dominating role of N-deacetylase/N-sulfotransferase 1 in forming domain structures in heparan sulfate. J Biol Chem 286:19768–19776PubMedCrossRefGoogle Scholar
  42. Spillmann D, Lindahl U (1994) Glycosaminoglycan-protein interactions: a question of specificity. Curr Opin Struct Biol 4:677–682CrossRefGoogle Scholar
  43. The I, Bellaiche Y, Perrimon N (1999) Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol Cell 4:633–639PubMedCrossRefGoogle Scholar
  44. Toma L, Berninsone P, Hirschberg CB (1998) The putative heparin-specific N-acetylglucosaminyl N-deacetylase/N-sulfotransferase also occurs in non-heparin-producing cells. J Biol Chem 273:22458–22465PubMedCrossRefGoogle Scholar
  45. Turnbull J, Drummond K, Huang Z, Kinnunen T, Ford-Perriss M, Murphy M, Guimond S (2003) Heparan sulphate sulphotransferase expression in mice and Caenorhabditis elegans. Biochem Soc Trans 31:343–348PubMedCrossRefGoogle Scholar
  46. Wang L, Fuster M, Sriramarao P, Esko JD (2005) Endothelial heparan sulfate deficiency impairs l-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nat Immunol 6:902–910PubMedCrossRefGoogle Scholar
  47. Wei Z, Swiedler SJ, Ishihara M, Orellana A, Hirschberg CB (1993) A single protein catalyzes both N-deacetylation and N-sulfation during the biosynthesis of heparan sulfate. Proc Natl Acad Sci USA 90:3885–3888PubMedCentralPubMedCrossRefGoogle Scholar
  48. Yabe T, Hata T, He J, Maeda N (2005) Developmental and regional expression of heparan sulfate sulfotransferase genes in the mouse brain. Glycobiology 15:982–993PubMedCrossRefGoogle Scholar
  49. Yasuda T, Mundy C, Kinumatsu T, Shibukawa Y, Shibutani T, Grobe K, Minugh-Purvis N, Pacifici M, Koyama E (2010) Sulfotransferase Ndst1 is needed for mandibular and TMJ development. J Dent Res 89:1111–1116PubMedCrossRefGoogle Scholar
  50. Zuberi RI, Ge XN, Jiang S, Bahaie NS, Kang BN, Hosseinkhani RM, Frenzel EM, Fuster MM, Esko JD, Rao SP, Sriramarao P (2009) Deficiency of endothelial heparan sulfates attenuates allergic airway inflammation. J Immunol 183:3971–3979PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Institute for Physiological Chemistry and PathobiochemistryUniversity Hospital Münster, Westfälische Wilhelms-Universität MünsterMünsterGermany

Personalised recommendations