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Glycobiology Advance Access originally published online on August 6, 2009
Glycobiology 2009 19(11):1197-1203; doi:10.1093/glycob/cwp110
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Dermatan 4-O-sulfotransferase 1 is pivotal in the formation of iduronic acid blocks in dermatan sulfate

Benny Pacheco, Marco Maccarana and Anders Malmström1

Department of Experimental Medical Science, BMC D12, Lund University, SE 221 84 Lund, Sweden

1 To whom correspondence should be addressed: Tel: +46-46-222-85-74; Fax: +46-46-211-34-17; e-mail: anders.malmstrom{at}med.lu.se

Received on March 11, 2009; revised on June 18, 2009; accepted on July 16, 2009

Chondroitin/dermatan sulfate is a highly complex linear polysaccharide ubiquitously found in the extracellular matrix and at the cell surface. Several of its functions, such as binding to growth factors, are mediated by domains composed of alternating iduronic acid and 4-O-sulfated N-acetylgalactosamine residues, named 4-O-sulfated iduronic acid blocks. These domains are generated by the action of two DS-epimerases, which convert D-glucuronic acid into its epimer L-iduronic acid, in close connection with 4-O-sulfation. In this study, dermatan sulfate structure was evaluated after downregulating or increasing dermatan 4-O-sulfotransferase 1 (D4ST-1) expression. siRNA-mediated downregulation of D4ST-1 in primary human lung fibroblasts led to a drastic specific reduction of iduronic acid blocks. No change of epimerase activity was found, indicating that the influence of D4ST-1 on epimerization is not due to an altered expression level of the DS-epimerases. Analysis of the dermatan sulfate chains showed that D4ST-1 is essential for the biosynthesis of the disulfated structure iduronic acid-2-O-sulfate-N-acetylgalactosamine-4-O-sulfate, thus confirmed to be strictly connected with the iduronic acid blocks. Also the biologically important residue hexuronic acid-N-acetylgalactosamine-4,6-O-disulfate considerably decreased after D4ST-1 downregulation. In conclusion, D4ST-1 is a key enzyme and is indispensable in the formation of important functional domains in dermatan sulfate and cannot be compensated by other 4-O-sulfotransferases.

Key words: chondroitin sulfate / dermatan sulfate / epimerase / iduronic acid / sulfotransferase


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 Mol. Cell. Biol.Home page
M. Maccarana, S. Kalamajski, M. Kongsgaard, S. P. Magnusson, A. Oldberg, and A. Malmstrom
Dermatan Sulfate Epimerase 1-Deficient Mice Have Reduced Content and Changed Distribution of Iduronic Acids in Dermatan Sulfate and an Altered Collagen Structure in Skin
Mol. Cell. Biol., October 15, 2009; 29(20): 5517 - 5528.
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