title: Directing the biological activities of heparan sulfate oligosaccharides using a chemoenzymatic approach.
abstract: Heparan sulfate (HS) and heparin are highly sulfated polysaccharides exhibiting essential physiological functions. The sulfation patterns determine the functional selectivity for HS and heparin. Chemical synthesis of HS, especially those larger than a hexasaccharide, remains challenging. Enzymatic synthesis of HS has recently gained momentum. Here we describe the divergent assembly of HS heptasaccharides and nonasaccharides from a common hexasaccharide precursor. The hexasaccharide precursor was synthesized via a chemical method. The subsequent elongation, sulfation and epimerization were completed by glycosyltransferases, HS sulfotransferases and epimerase. Using the synthesized heptasaccharides, we discovered that the iduronic acid is critical for binding to fibroblast growth factor-2. We also designed a synthetic path to prepare a nonasaccharide with an antithrombin-binding affinity of 3 nM. Our method demonstrated the feasibility of combining chemical and enzymatic synthesis to prepare structurally defined HS oligosaccharides with desired biological activities.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University ofNorth Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Renpeng
authors.initials: R
authors.lastname: Liu
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.forename: Xuefei
authors.initials: X
authors.lastname: Huang
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
mesh_terms: D000991:Antithrombins / Q000737:chemistry; D055162:Biocatalysis; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry; D016695:Glycosyltransferases / Q000737:chemistry; D006497:Heparan Sulfate / Q000138:chemical synthesis* / Q000737:chemistry; D008969:Molecular Sequence Data; D011485:Protein Binding; D019998:Racemases and Epimerases / Q000737:chemistry; D015238:Sulfotransferases / Q000737:chemistry; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000991:Antithrombins; D016222:Fibroblast Growth Factor 2; D016695:Glycosyltransferases; D006497:Heparan Sulfate; D019998:Racemases and Epimerases; D015238:Sulfotransferases; D013463:Sulfuric Acid Esters