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Applied Microbiology and Biotechnology

, Volume 74, Issue 2, pp 263–272 | Cite as

Anticoagulant heparan sulfate: structural specificity and biosynthesis

  • Jian LiuEmail author
  • Lars C. Pedersen
Mini-Review

Abstract

Heparan sulfate (HS) is present on the surface of endothelial and surrounding tissues in large quantities. It plays important roles in regulating numerous functions of the blood vessel wall, including blood coagulation, inflammation response, and cell differentiation. HS is a highly sulfated polysaccharide containing glucosamine and glucuronic/iduronic acid repeating disaccharide units. The unique sulfated saccharide sequences of HS determine its specific functions. Heparin, an analog of HS, is the most commonly used anticoagulant drug. Because of its wide range of biological functions, HS has become an interesting molecule to biochemists, medicinal chemists, and developmental biologists. In this review, we summarize recent progress toward understanding the interaction between HS and blood-coagulating factors, the biosynthesis of anticoagulant HS and the mechanism of action of HS biosynthetic enzymes. Furthermore, knowledge of the biosynthesis of HS facilitates the development of novel enzymatic approaches to synthesize HS from bacterial capsular polysaccharides and to produce polysaccharide end products with high specificity for the biological target. These advancements provide the foundation for the development of polysaccharide-based therapeutic agents.

Keywords

Heparin Heparan sulfate Sulfotransferase Anticoagulant Oligosaccharide Herpes simplex virus 

Notes

Acknowledgements

The authors are grateful to A.F. Moon and Dr. L.G. Pedersen for critical reading of the manuscript. The Liu lab is supported by a grant from the National Institutes of Health (AI050050). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

References

  1. Aikawa J-i, Grobe K, Tsujimoto M, Esko JD (2001) Multiple isozymes of heparan sulfates/heparin GlcNAc N-deacetylase/GlcN N-sulfotransferase: structure and activity of the fourth member, NDST4. J Biol Chem 276:5876–5882CrossRefGoogle Scholar
  2. Ashikari-Hada S, Habuchi H, Kariya Y, Itoh N, Reddi AH, Kimata K (2004) Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. J Biol Chem 279:12346–12354CrossRefGoogle Scholar
  3. Atha DH, Lormeau J-C, Petitou M, Rosenberg RD, Choay J (1985) Contribution of monosaccharide residues in heparin binding to antithrombin III. Biochemistry 24:6723–6729CrossRefGoogle Scholar
  4. Avci FY, Karst NA, Linhardt RJ (2003) Synthetic oligosaccharides as heparin-mimetics displaying anticoagulant properties. Curr Pharm Des 9:2323–2335CrossRefGoogle Scholar
  5. Balagurunathan K, Beeler DL, Lech M, Wu ZL, Rosenberg RD (2003a) Chemoenzymatic synthesis of classical and non-classical anticoagulant heparan sulfate polysaccharides. J Biol Chem 278:52613–52621CrossRefGoogle Scholar
  6. Balagurunathan K, Lech MZ, Beeler DL, Wu ZL, Rosenberg RD (2003b) Enzymatic synthesis of antithrombin III-binding heparan sulfate pentasaccharide. Nat Biotechnol 21:1343–1346CrossRefGoogle Scholar
  7. Becker RC (2004) Optimizing heparin compounds: a working construct for future antithrombotic drug development. J Thromb Thrombolysis 18:55–58CrossRefGoogle Scholar
  8. Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777CrossRefGoogle Scholar
  9. Burkart MD, Izumi M, Chapman E, Lin C, Wong C (2000) Regeneration of PAPS for the enzymatic synthesis of sulfated oligosaccharides. J Org Chem 65:5565–5574CrossRefGoogle Scholar
  10. Chen J, Duncan MB, Carrick K, Pope M, Liu J (2003) Biosynthesis of 3-O-sulfated heparan sulfate: unique substrate specificity of heparan sulfate 3-O-sulfotransferase isoform 5. Glycobiology 13:785–794CrossRefGoogle Scholar
  11. Chen J, Avci FY, Muñoz EM, McDowell LM, Chen M, Pedersen LC, Zhang L, Linhardt RJ, Liu J (2005) Enzymatically redesigning of biologically active heparan sulfate. J Biol Chem 280:42817–42825CrossRefGoogle Scholar
  12. Coombe DR, Kett WC (2005) Heparan sulfate-protein interactions: therapeutic potential through structure–function insights. Cell Mol Life Sci 62:410–424CrossRefGoogle Scholar
  13. Das S, Mallet J, Esnault J, Driguez P, Duchaussoy P, Sizun P, Herault J, Herbert J, Petitou M, Sinay P (2001) Synthesis of conformationally locked L-iduronic acid derivatives: direct evidence for a critical role of the skew-boat 2S0 conformer in the activation of antithrombin by heparin. Chemistry 7:4821–4834CrossRefGoogle Scholar
  14. de Paz JL, Noti C, Seeberger PH (2006) Microarrays of synthetic heparin oligosaccharides. J Am Chem Soc 128:2766–2767CrossRefGoogle Scholar
  15. Dementiev A, Petitou M, Herbert J-M, Gettins PG (2004) The ternary complex of antithrombin–anhydrothrombin–heparin reveals the basis of inhibitor specificity. Nat Struct Biol 11:867–863CrossRefGoogle Scholar
  16. Duncan MB, Chen J, Krise JP, Liu J (2004) The biosynthesis of anticoagulant heparan sulphate by the heparan sulphate 3-O-sulphotransferase isoform 5. Biochim Biophys Acta 1671:34–43Google Scholar
  17. Edavettal SC, Lee KA, Negishi M, Linhardt RJ, Liu J, Pedersen LC (2004) Crystal structure and mutational analysis of heparan sulfate 3-O-sulfotransferase isoform 1. J Biol Chem 279:25789–25797CrossRefGoogle Scholar
  18. Esko JD, Selleck SB (2002) Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 71:435–471CrossRefGoogle Scholar
  19. Ferro V, Don R (2003) The development of the novel angiogenesis inhibitor PI-88 as an anticancer drug. Australas Biotechnol 13:38–39Google Scholar
  20. Gettins PG (2002) Serpin structure, mechanism, and function. Chem Rev 102:4751–4803CrossRefGoogle Scholar
  21. Habuchi H, Habuchi O, Kimata K (1995) Purification and characterization of heparan sulfate 6-sulfotransferase from the culture medium of Chinese hamster ovary cells. J Biol Chem 270:4172CrossRefGoogle Scholar
  22. Habuchi H, Tanaka M, Habuchi O, Yoshida K, Suzuki H, Ban K, Kimata K (2000) The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine. J Biol Chem 275:2859–2868CrossRefGoogle Scholar
  23. Hacker U, Nybakken K, Perrimon N (2005) Heparan sulfate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol 6:530–541CrossRefGoogle Scholar
  24. HajMohammadi S, Enjyoji K, Princivalle M, Christi P, Lech M, Beeler DL, Rayburn H, Schwartz JJ, Barzegar S, de Agostini AI, Post MJ, Rosenberg RD, Shworak NW (2003) Normal levels of anticoagulant heparan sulfate are not essential for normal hemostasis. J Clin Invest 111:989–999CrossRefGoogle Scholar
  25. Herbert JM, Herault JP, Bernat A, Savi P, Schaeffer P, Driguez PA, Duchaussov P, Petitou M (2001) SR 123781A, a synthetic heparin mimetic. Thromb Haemost 85:852–860Google Scholar
  26. Hirsh J, O’Donnell M, Weitz JI (2005) New anticoagulants. Blood 105:453–463CrossRefGoogle Scholar
  27. Ishihara M, Guo Y, Wei Z, Yang Z, Swiedler SJ, Orellana A, Hirschberg CB (1993) Regulation of biosynthesis of the basic fibroblast growth factor binding domains of heparan sulfate by heparan sulfate-N-deacetylase/N-sulfotransferase expression. J Biol Chem 268:20091–20095Google Scholar
  28. Jin L, Abrahams P, Skinner R, Petitou M, Pike RN, Carrell RW (1997) The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci USA 94:14683–14688CrossRefGoogle Scholar
  29. Kelton JG (2002) Heparin-induced thrombocytopenia: an overview. Blood Rev 16:77–80CrossRefGoogle Scholar
  30. Kobayashi M, Habuchi H, Habuchi O, Saito M, Kimata K (1996) Purification and characterization of heparan sulfate 2-sulfotransferase from cultured Chinese hamster ovary cells. J Biol Chem 271:7645–7653CrossRefGoogle Scholar
  31. Kraulis PJ (1991) MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J Appl Crystallogr 24:946–950CrossRefGoogle Scholar
  32. Kuberan B, Beeler DL, Lawrence R, Lech M, Rosenberg R (2003) Rapid two-step synthesis of mitrin from heparosan: a replacement for heparin. J Am Chem Soc 125:12424–12425CrossRefGoogle Scholar
  33. Lee JC, Lu XA, Kulkarni SS, Wen YS, Hung SC (2004) Synthesis of heparin oligosaccharides. J Am Chem Soc 126:476–477CrossRefGoogle Scholar
  34. Li W, Johnson DJ, Esmon CT, Huntington JA (2004) Structure of the antithrombin–thrombin–heparin ternary complex reveals the anti-thrombotic mechanism of heparin. Nat Struct Mol Biol 11:857–862CrossRefGoogle Scholar
  35. Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K (1998) The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 273:26265–26268CrossRefGoogle Scholar
  36. Lindahl U, Kusche-Gullberg M, Kjellen L (1998) Regulated diversity of heparan sulfate. J Biol Chem 273:24979–24982CrossRefGoogle Scholar
  37. Lindahl U, Li J, Kusche-Gullberg M, Salmivirta M, Alaranta S, Veromaa T, Emies J, Roberts I, Taylor C, Oreste P et al (2005) Generation of “neoheparin” from E. Coli K5 capsular polysaccharide. J Med Chem 48:349–352CrossRefGoogle Scholar
  38. Liu J, Rosenberg RD (2002) Heparan sulfate D-glucosaminyl 3-O-sulfotransferase. In: N Taniguchi, M Fukuda (eds) Handbook of glycosyltransferases and their related genes. Springer, Berlin Heidelberg New York, pp 475–483Google Scholar
  39. Liu J, Thorp SC (2002) Heparan sulfate and the roles in assisting viral infections. Med Res Rev 22:1–25CrossRefGoogle Scholar
  40. Liu J, Shworak NW, Fritze LMS, Edelberg JM, Rosenberg RD (1996) Purification of heparan sulfate D-glucosaminyl 3-O-sulfotransferase. J Biol Chem 271:27072–27082CrossRefGoogle Scholar
  41. Liu J, Shworak NW, Sinaÿ P, Schwartz JJ, Zhang L, Fritze LMS, Rosenberg RD (1999) Expression of heparan sulfate D-glucosaminyl 3-O-sulfotransferase isoforms reveals novel substrate specificities. J Biol Chem 274:5185–5192CrossRefGoogle Scholar
  42. McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F (1998) The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet 19:158–161CrossRefGoogle Scholar
  43. Merritt EA, Bacon DJ (1997) Raster3D: photorealistic molecular graphics. Methods Enzymol 277:505–524Google Scholar
  44. Mikhailov D, Mayo KH, Pervin A, Linhardt RJ (1996) 13C-NMR relaxation study of heparin–disaccharide interactions with tripeptide GRG and GKG. Biochem J 315:447–454Google Scholar
  45. Moon A, Edavettal SC, Krahn JX, Munoz EM, Negishi M, Linhardt RJ, Liu J, Pedersen LC (2004) Structural analysis of the sulfotransferase (3-OST-3) involved in the biosynthesis of an entry receptor of herpes simplex virus 1. J Biol Chem 279:45185–45193CrossRefGoogle Scholar
  46. Mulloy B, Forster M (2000) Conformation and dynamics of heparin and heparan sulfate. Glycobiology 10:1147–1156CrossRefGoogle Scholar
  47. Nyberg K, Ekblad M, Bergstrom T, Freeman C, Parish CR, Ferro V, Trybala E (2004) The low molecular weight heparan sulfate-mimetic, PI-88, inhibits cell-to-cell spread of herpes simplex virus. Antiviral Res 63:15–24CrossRefGoogle Scholar
  48. Oosta GM, Gardner WT, Beeler DL, Rosenberg R (1981) Multiple functional domains of the heparin molecule. Proc Natl Acad Sci USA 78:829–833CrossRefGoogle Scholar
  49. Petitou M, van Boeckel CAA (1992) Chemical synthesis of heparin fragments and analogues. Fortschr Chem Org Naturst 60:143–210Google Scholar
  50. Petitou M, van Boeckel CAA (2004) A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next? Angew Chem Int Ed 43:3118–3133CrossRefGoogle Scholar
  51. Petitou M, Herault L-P, Bernat A, Driguez P-A, Duchaussoy P, Lormeau J-C, Herbert J-M (1999) Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 398:417–422CrossRefGoogle Scholar
  52. Raman R, Sasisekharan V, Sasisekharan R (2005) Structural insights into biological roles of protein–glycosaminoglycan interactions. Chem Biol 12:267–277CrossRefGoogle Scholar
  53. Rosenberg RD, Showrak NW, Liu J, Schwartz JJ, Zhang L (1997) Heparan sulfate proteoglycans of the cardiovascular system: specific structures emerge but how is synthesis regulated? J Clin Invest 99:2062–2070CrossRefGoogle Scholar
  54. Sanderson RD, Yang Y, Suva LJ, Kelly T (2004) Heparan sulfate proteglycans and heparanase—partners in osteolytic tumor growth and metastasis. Matrix Biol 23:341–352CrossRefGoogle Scholar
  55. Sasisekharan R, Shriver Z, Venkataraman G, Narayanasami U (2002) Roles of heparin-sulphate glycosaminoglycans in cancer. Nat Rev Cancer 2:521–528CrossRefGoogle Scholar
  56. Shukla D, Liu J, Blaiklock P, Shworak NW, Bai X, Esko JD, Cohen GH, Eisenberg RJ, Rosenberg RD, Spear PG (1999) A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry. Cell 99:13–22CrossRefGoogle Scholar
  57. Shworak NW, Liu J, Fritze LMS, Schwartz JJ, Zhang L, Logeart D, Rosenberg RD (1997) Molecular cloning and expression of mouse and human cDNAs encoding heparan sulfate D-glucosaminyl 3-O-sulfotransferase. J Biol Chem 272:28008–28019CrossRefGoogle Scholar
  58. Shworak NW, Liu J, Petros LM, Zhang L, Kobayashi M, Copeland NG, Jenkins NA, Rosenberg RD (1999) Diversity of the extensive heparan sulfate D-glucosaminyl 3-O-sulfotransferase (3-OST) multigene family. J Biol Chem 274:5170–5184CrossRefGoogle Scholar
  59. Smeds E, Habuchi H, Do A-T, Hjertson E, Grundberg H, Kimata K, Lindahl U, Kusche-Gullberg M (2003) Substrate specificities of mouse heparan sulphate glucosaminyl 6-O-sulfotransferases. Biochem J 372(Pt 2):371–380CrossRefGoogle Scholar
  60. Taylor KR, Gallo RL (2006) Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J 20:9–22CrossRefGoogle Scholar
  61. Xia G, Chen J, Tiwari V, Ju W, Li J-P, Malmström A, Shukla D, Liu J (2002) Heparan sulfate 3-O-sulfotransferase isoform 5 generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1. J Biol Chem 277:37912–37919CrossRefGoogle Scholar
  62. Xu D, Tiwari V, Xia G, Clement C, Shukla D, Liu J (2005) Characterization of heparan sulfate 3-O-sulfotransferase isoform 6 and its role in assisting the entry of herpes simplex virus, type 1. Biochem J 385:451–459CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Division of Medicinal Chemistry and Natural Products, School of PharmacyUniversity of North CarolinaChapel HillUSA
  2. 2.Laboratory of Structural Biology, the National Institute of Environmental Health SciencesNational Institutes of HealthResearch Triangle ParkUSA

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