Recombinant dermatan sulfate is a potent activator of heparin cofactor II-dependent inhibition of thrombin
(2019) In Glycobiology 29(6). p.446-451- Abstract
The glycosaminoglycan dermatan sulfate (DS) is a well-known activator of heparin cofactor II-dependent inactivation of thrombin. In contrast to heparin, dermatan sulfate has never been prepared recombinantly from material of non-animal origin. Here we report on the enzymatic synthesis of structurally well-defined DS with high anticoagulant activity. Using a microbial K4 polysaccharide and the recombinant enzymes DS-epimerase 1, dermatan 4-O-sulfotransferase 1, uronyl 2-O-sulfotransferase and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase, several new glycostructures have been prepared, such as a homogenously sulfated IdoA-GalNAc-4S polymer and its 2-O-, 6-O- and 2,6-O-sulfated derivatives. Importantly, the recombinant highly... (More)
The glycosaminoglycan dermatan sulfate (DS) is a well-known activator of heparin cofactor II-dependent inactivation of thrombin. In contrast to heparin, dermatan sulfate has never been prepared recombinantly from material of non-animal origin. Here we report on the enzymatic synthesis of structurally well-defined DS with high anticoagulant activity. Using a microbial K4 polysaccharide and the recombinant enzymes DS-epimerase 1, dermatan 4-O-sulfotransferase 1, uronyl 2-O-sulfotransferase and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase, several new glycostructures have been prepared, such as a homogenously sulfated IdoA-GalNAc-4S polymer and its 2-O-, 6-O- and 2,6-O-sulfated derivatives. Importantly, the recombinant highly 2,4-O-sulfated DS inhibits thrombin via heparin cofactor II, approximately 20 times better than heparin, enabling manipulation of vascular and extravascular coagulation. The potential of this method can be extended to preparation of specific structures that are of importance for binding and activation of cytokines, and control of inflammation and metastasis, involving extravasation and migration.
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- author
- Tykesson, Emil LU ; Maccarana, Marco LU ; Thorsson, Hanna LU ; Liu, Jian ; Malmström, Anders LU ; Ellervik, Ulf LU and Westergren-Thorsson, Gunilla LU
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Glycobiology
- volume
- 29
- issue
- 6
- pages
- 446 - 451
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85066842259
- pmid:30869126
- ISSN
- 1460-2423
- DOI
- 10.1093/glycob/cwz019
- project
- Small molecules that interfere with the biosynthesis of dermatan sulfate for exploration of cell surface carbohydrates and use as cancer therapy
- language
- English
- LU publication?
- yes
- id
- 11ab4973-df73-4f93-9f2c-5bc0c2c77c9c
- date added to LUP
- 2019-05-20 15:25:55
- date last changed
- 2024-09-18 20:43:43
@article{11ab4973-df73-4f93-9f2c-5bc0c2c77c9c, abstract = {{<p>The glycosaminoglycan dermatan sulfate (DS) is a well-known activator of heparin cofactor II-dependent inactivation of thrombin. In contrast to heparin, dermatan sulfate has never been prepared recombinantly from material of non-animal origin. Here we report on the enzymatic synthesis of structurally well-defined DS with high anticoagulant activity. Using a microbial K4 polysaccharide and the recombinant enzymes DS-epimerase 1, dermatan 4-O-sulfotransferase 1, uronyl 2-O-sulfotransferase and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase, several new glycostructures have been prepared, such as a homogenously sulfated IdoA-GalNAc-4S polymer and its 2-O-, 6-O- and 2,6-O-sulfated derivatives. Importantly, the recombinant highly 2,4-O-sulfated DS inhibits thrombin via heparin cofactor II, approximately 20 times better than heparin, enabling manipulation of vascular and extravascular coagulation. The potential of this method can be extended to preparation of specific structures that are of importance for binding and activation of cytokines, and control of inflammation and metastasis, involving extravasation and migration.</p>}}, author = {{Tykesson, Emil and Maccarana, Marco and Thorsson, Hanna and Liu, Jian and Malmström, Anders and Ellervik, Ulf and Westergren-Thorsson, Gunilla}}, issn = {{1460-2423}}, language = {{eng}}, number = {{6}}, pages = {{446--451}}, publisher = {{Oxford University Press}}, series = {{Glycobiology}}, title = {{Recombinant dermatan sulfate is a potent activator of heparin cofactor II-dependent inhibition of thrombin}}, url = {{http://dx.doi.org/10.1093/glycob/cwz019}}, doi = {{10.1093/glycob/cwz019}}, volume = {{29}}, year = {{2019}}, }