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J. Biol. Chem., Vol. 281, Issue 47, 35727-35734, November 24, 2006

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Enzymatically Active N-Deacetylase/N-Sulfotransferase-2 Is Present in Liver but Does Not Contribute to Heparan Sulfate N-Sulfation^*

From the Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden

Heparan sulfate (HS) proteoglycans influence embryonic development through interactions with growth factors and morphogens. The interactions depend on HS structure, which is largely determined during biosynthesis by Golgi enzymes. NDST (glucosaminyl N-deacetylase/N-sulfotransferase), responsible for HS N-sulfation, is a key enzyme directing further modifications including O-sulfation. To elucidate the roles of the different NDST isoforms in HS biosynthesis, we took advantage of mice with targeted mutations in NDST1 and NDST2 and used liver as our model organ. Of the four NDST isoforms, only NDST1 and NDST2 transcripts were shown to be expressed in control liver. The absence of NDST1 or NDST2 in the knock-out mice did not affect transcript levels of other NDST isoforms or other HS modification enzymes. Although the sulfation level of HS synthesized in NDST1^–/– mice was drastically lowered, liver HS from wild-type mice, from NDST1^+/–, NDST2^–/–, and NDST1^+/–/NDST2^–/– mice all had the same structure despite greatly reduced NDST enzyme activity (30% of control levels in NDST1^+/–/NDST2^–/– embryonic day 18.5 embryos). Enzymatically active NDST2 was shown to be present in similar amounts in wild-type, NDST1^–/–, and NDST1^+/– embryonic day 18.5 liver. Despite the substantial contribution of NDST2 to total NDST enzyme activity in embryonic day 18.5 liver (40%), its presence did not appear to affect HS structure as long as NDST1 was also present. In NDST1^–/– embryonic day 18.5 liver, in contrast, NDST2 was responsible for N-sulfation of the low sulfated HS. A tentative model to explain these results is presented.

Received for publication, May 1, 2006 , and in revised form, August 17, 2006.

^* This work was funded by the Swedish Research Council, the programme "Glycoconjugates in Biological Systems" sponsored by the Swedish Foundation for Strategic Research, Polysackaridforskning 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.

¹ To whom correspondence should be addressed: Dept. of Medical Biochemistry and Microbiology, The Biomedical Ctr., Box 582, SE-751 23 Uppsala, Sweden. Tel.: 46-18-471-4217; Fax: 46-18-471-4244; E-mail: lena.kjellen{at}imbim.uu.se.

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