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Recombinant dermatan sulfate is a potent activator of heparin cofactor II-dependent inhibition of thrombin

Tykesson, Emil LU ; Maccarana, Marco LU ; Thorsson, Hanna LU ; Liu, Jian ; Malmström, Anders LU ; Ellervik, Ulf LU and Westergren-Thorsson, Gunilla LU (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
organization
publishing date
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
language
English
LU publication?
yes
id
11ab4973-df73-4f93-9f2c-5bc0c2c77c9c
date added to LUP
2019-05-20 15:25:55
date last changed
2019-07-09 04:45:47
@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},
}