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Gene Review

NDST1  -  N-deacetylase/N-sulfotransferase (heparan...

Homo sapiens

Synonyms: Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1, Glucosaminyl N-deacetylase/N-sulfotransferase 1, HSNST 1, HSST, HSST1, ...
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Disease relevance of NDST1

  • Two genes encoding NDST isozymes have been described, one from rat liver (NDST1) and another from murine mastocytoma (NDST2) [1].
  • The assay is based on the recognition of NDST-generated N-unsubstituted glucosamine units in Escherichia coli K5 capsular polysaccharide or in HSs by monoclonal antibody JM-403 [2].
  • Altered expression of NDST-1 messenger RNA in puromycin aminonucleoside nephrosis [3].
  • In contrast, on day 35, when PAN-treated rats recovered from proteinuria, we noted no differences in glomerular expression of NDST-1 mRNA and staining intensity for N-sulfated GAG chains on GBM between PAN-treated rats and controls [3].
  • In this study, we demonstrate that inactivation of the heparan sulfate biosynthetic gene Ndst1 resulted in invagination defects of the early lens and in the disruption of lens-determination gene expression, leading to severe lens hypoplasia or anophthalmia [4].

High impact information on NDST1

  • Heparan sulfate biosynthetic gene Ndst1 is required for FGF signaling in early lens development [4].
  • Enzymatically active NDST2 was shown to be present in similar amounts in wild-type, NDST1(-/-), and NDST1(+/-) embryonic day 18.5 liver [5].
  • These reactions are catalyzed by GlcNAc N-deacetylase/N-sulfotransferase (NDST), a monomeric enzyme with two catalytic activities [1].
  • Heparan sulfate N-deacetylase/N-sulfotransferase (HSNST) catalyzes the first and obligatory step in the biosynthesis of heparan sulfates and heparin [6].
  • The crystal structure of the sulfotransferase domain (NST1) of human HSNST-1 has been determined at 2.3-A resolution in a binary complex with 3'-phosphoadenosine 5'-phosphate (PAP) [6].

Chemical compound and disease context of NDST1

  • On day 10, when significant proteinuria developed, the ratios of glomerular expression of NDST-1 mRNA against glyceraldehyde-phosphate dehydrogenase mRNA in PAN-treated rats were decreased to 48% +/- 6% of those in controls (P<.05) [3].

Biological context of NDST1

  • We have introduced point mutations into NDST-1 cDNA, which selectively destroy the N-deacetylase or N-sulfotransferase activity of the enzyme [Wei, Z., and Swiedler, S. J. (1999) J. Biol. Chem. 274, 1966-70 and Sueyoshi, T., et al. (1998) FEBS Lett. 433, 211-4] [7].
  • Distinct effects on heparan sulfate structure by different active site mutations in NDST-1 [7].
  • NDST-1 and -2 have a wide and largely overlapping tissue distribution, but it is not known if they can act on the same heparan sulfate chain [7].
  • Transfection of mutant NDST-1 lacking N-deacetylase activity had no effect on heparan sulfate sulfation, while cells expressing wild-type enzyme or NDST-1 lacking N-sulfotransferase activity both resulted in the production of oversulfated heparan sulfate [7].
  • Substrate specificity and potential product inhibition of the NDST isoforms 1 and 2 were analyzed by comparing lysates of human 293 kidney cells stably transfected with mouse NDST-1 or -2 [2].

Anatomical context of NDST1

  • In mesangial cells (MC), NDST expression was not influenced by glucose [8].
  • CONCLUSIONS: Since NDST 1 and 2 are not differentially expressed in patients with or without nephropathy and, in MC, the mRNA expression hereof is not influenced by glucose as in skin fibroblasts, our data do not support the Steno hypothesis [8].
  • Stable 293 cell lines expressing the NDST-1 mutants were then generated [7].
  • To this end, we prepared a rabbit polyclonal antibody against the cytosolic N-terminal oligopeptide of the enzyme heparan glucosaminyl N-deacetylase/N-sulphotransferase (HSST), a specific marker for Golgi apparatus [9].
  • This study demonstrated that pro-inflammatory cytokines can increase NDST expression leading to increased sulphation of HS and a corresponding increase in sequestration of functional RANTES at the apical surface of endothelial cells [10].

Associations of NDST1 with chemical compounds

  • In a Chinese hamster ovary cell mutant exhibiting reduced N-sulfotransferase activity and reduced sulfation of heparan sulfate (Bame, K. J., and Esko, J. D. (1989) J. Biol. Chem. 264, 8059-8065), expression of NDST1 was greatly reduced, but NDST2 was expressed normally, suggesting that both enzymes are involved in heparan sulfate assembly [1].
  • In the non-diabetic group only, 25 mM D-glucose significantly increased NDST 1 mRNA expression (P<0.01) [8].
  • The modification reactions are initiated by glucosaminyl N-deacetylase/N-sulfotransferase (NDST), a bifunctional enzyme that removes N-acetyl groups from selected N-acetyl-d-glucosamine units followed by N-sulfation of the generated free amino groups [7].
  • In addition, we show that oversulfation of heparan sulfate produced by cells tranfected with wild-type NDST-1 or the mutant lacking N-sulfotranferase activity results in decreased sulfation of chondroitin sulfate [7].
  • Comparison of various HS preparations and the unsulfated K5 polysaccharide as substrates indicate that both NDST-1 and -2 can differentially N-sulfate polysaccharides already modified to some extent by various other enzymes involved in HS/heparin synthesis [2].

Other interactions of NDST1

  • The level of N-sulfation increased from 40% in control cells to 60% and 80%, respectively, in NDST-1 and NDST-2 transfected cells [11].
  • Here we describe an efficient dot-blot assay for high-throughput screening of two enzymes, heparan sulfate N-deacetylase/N-sulfotransferase (NDST-1) and high-endothelial cell GlcNAc-6-sulfotransferase (HEC-GlcNAc-6-ST) [12].

Analytical, diagnostic and therapeutic context of NDST1


  1. Molecular cloning and expression of a third member of the heparan sulfate/heparin GlcNAc N-deacetylase/ N-sulfotransferase family. Aikawa, J., Esko, J.D. J. Biol. Chem. (1999) [Pubmed]
  2. Antibody-based assay for N-deacetylase activity of heparan sulfate/heparin N-deacetylase/N-sulfotransferase (NDST): novel characteristics of NDST-1 and -2. van den Born, J., Pikas, D.S., Pisa, B.J., Eriksson, I., Kjellen, L., Berden, J.H. Glycobiology (2003) [Pubmed]
  3. Altered expression of NDST-1 messenger RNA in puromycin aminonucleoside nephrosis. Nakayama, K., Natori, Y., Sato, T., Kimura, T., Sugiura, A., Sato, H., Saito, T., Ito, S., Natori, Y. J. Lab. Clin. Med. (2004) [Pubmed]
  4. Heparan sulfate biosynthetic gene Ndst1 is required for FGF signaling in early lens development. Pan, Y., Woodbury, A., Esko, J.D., Grobe, K., Zhang, X. Development (2006) [Pubmed]
  5. Enzymatically active N-deacetylase/n-sulfotransferase-2 is present in liver but does not contribute to heparan sulfate N-sulfation. Ledin, J., Ringvall, M., Thuveson, M., Eriksson, I., Wil??n, M., Kusche-Gullberg, M., Forsberg, E., Kjell??n, L. J. Biol. Chem. (2006) [Pubmed]
  6. Crystal structure of the sulfotransferase domain of human heparan sulfate N-deacetylase/ N-sulfotransferase 1. Kakuta, Y., Sueyoshi, T., Negishi, M., Pedersen, L.C. J. Biol. Chem. (1999) [Pubmed]
  7. Distinct effects on heparan sulfate structure by different active site mutations in NDST-1. Bengtsson, J., Eriksson, I., Kjellén, L. Biochemistry (2003) [Pubmed]
  8. Influence of high glucose concentrations on the expression of glycosaminoglycans and N-deacetylase/N-sulphotransferase mRNA in cultured skin fibroblasts from diabetic patients with or without nephropathy. Yard, B., Feng, Y., Keller, H., Mall, C., van Der Woude, F. Nephrol. Dial. Transplant. (2002) [Pubmed]
  9. Immunopurification of Golgi vesicles by magnetic sorting. Mura, C.V., Becker, M.I., Orellana, A., Wolff, D. J. Immunol. Methods (2002) [Pubmed]
  10. Endothelial inflammation: the role of differential expression of N-deacetylase/N-sulphotransferase enzymes in alteration of the immunological properties of heparan sulphate. Carter, N.M., Ali, S., Kirby, J.A. J. Cell. Sci. (2003) [Pubmed]
  11. Overexpression of different isoforms of glucosaminyl N-deacetylase/N-sulfotransferase results in distinct heparan sulfate N-sulfation patterns. Pikas, D.S., Eriksson, I., Kjellén, L. Biochemistry (2000) [Pubmed]
  12. A 96-well dot-blot assay for carbohydrate sulfotransferases. Verdugo, D.E., Bertozzi, C.R. Anal. Biochem. (2002) [Pubmed]
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