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J. Biol. Chem., Vol. 279, Issue 41, 42355-42358, October 8, 2004

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Heparan Sulfate Synthesized by Mouse Embryonic Stem Cells Deficient in NDST1 and NDST2 Is 6-O-Sulfated but Contains No N-Sulfate Groups^*

Katarina Holmborn, Johan Ledin, Emanuel Smeds, Inger Eriksson, Marion Kusche-Gullberg, and Lena Kjellén

From the Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-751 23 Uppsala, Sweden

Heparan sulfate structure differs significantly between various cell types and during different developmental stages. The diversity is created during biosynthesis by sulfotransferases, which add sulfate groups to the growing chain, and a C5-epimerase, which converts selected glucuronic acid residues to iduronic acid. All these modifications are believed to depend on initial glucosamine N-sulfation carried out by the enzyme glucosaminyl N-deacetylase/N-sulfotransferase (NDST). Here we report that heparan sulfate synthesized by mouse embryonic stem cells deficient in NDST1 and NDST2 completely lacks N-sulfation but still contains 6-O-sulfate groups, demonstrating that 6-O-sulfation can occur without prior N-sulfation. Reverse transcriptase-PCR analysis indicates that all three identified 6-O-sulfotransferases are expressed by the cells, 6-O-sulfotransferase-1 being the dominating form. The 6-O-sulfated polysaccharide lacking N-sulfate groups also contains N-unsubstituted glucosamine units, raising questions about how these units are generated.

Received for publication, August 5, 2004 , and in revised form, August 19, 2004.

^* This work was supported by grants from the Swedish Research Council, the program "Glycoconjugates in Biological Systems" sponsored by the Swedish Foundation for Strategic Research, Polysackarid-forskning AB, and Gustaf V:s 80-årsfond. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 46-18-471-4217; Fax: 46-18-471-4244; E-mail: lena.kjellen{at}imbim.uu.se.

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