Using engineered 6--sulfotransferase to improve the synthesis of anticoagulant heparin
Heparan sulfate (HS) and heparin are sulfated polysaccharides exhibiting diverse physiological functions. HS 6- O -sulfotransferase (6-OST) is a HS biosynthetic enzyme that transfers a sulfo group to the 6-OH position of glucosamine to synthesize HS with desired biological activities. Chemoenzymatic...
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Published in | Organic & biomolecular chemistry Vol. 18; no. 4; pp. 894 - 812 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
21.10.2020
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Online Access | Get full text |
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Summary: | Heparan sulfate (HS) and heparin are sulfated polysaccharides exhibiting diverse physiological functions. HS 6-
O
-sulfotransferase (6-OST) is a HS biosynthetic enzyme that transfers a sulfo group to the 6-OH position of glucosamine to synthesize HS with desired biological activities. Chemoenzymatic synthesis is a widely adopted method to obtain HS oligosaccharides to support biological studies. However, this method is unable to synthesize all possible structures due to the specificity of natural enzymes. Here, we report the use of an engineered 6-OST to achieve fine control of the 6-
O
-sulfation. Unlike wild type enzyme, the engineered 6-OST only sulfates the non-reducing end glucosamine residue. Utilizing the engineered enzyme and wild type enzyme, we successfully completed the synthesis of five hexasaccharides and one octasaccharide differing in 6-
O
-sulfation patterns. We also identified a hexasaccharide construct as a new anticoagulant drug candidate. Our results demonstrate the feasibility of using an engineered HS biosynthetic enzyme to prepare HS-based therapeutics.
Heparan sulfate (HS) and heparin are sulfated polysaccharides exhibiting diverse physiological functions. |
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Bibliography: | 10.1039/d0ob01736a Electronic supplementary information (ESI) available: Experimental procedures, additional synthetic routes and data for compound characterization (NMR, ESI-MS spectra, HPLC analysis). See DOI |
ISSN: | 1477-0520 1477-0539 |
DOI: | 10.1039/d0ob01736a |