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J. Biol. Chem., Vol. 283, Issue 43, 28881-28887, October 24, 2008

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Inhibition of Heparan Sulfate and Chondroitin Sulfate Proteoglycan Biosynthesis^*

Dinesh R. Garud¹², Vy M. Tran¹, Xylophone V. Victor^¶, Mamoru Koketsu^||, and Balagurunathan Kuberan^¶3

From the Department of Chemistry, Faculty of Engineering, and the ^||Division of Instrumental Analysis, Life Science Research Center, Gifu University, Gifu 501-1193, Japan and the Departments of Bioengineering and ^¶Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112

Proteoglycans (PGs) are composed of a protein moiety and a complex glycosaminoglycan (GAG) polysaccharide moiety. GAG chains are responsible for various biological activities. GAG chains are covalently attached to serine residues of the core protein. The first step in PG biosynthesis is xylosylation of certain serine residues of the core protein. A specific linker tetrasaccharide is then assembled and serves as an acceptor for elongation of GAG chains. If the production of endogenous GAG chains is selectively inhibited, one could determine the role of these endogenous molecules in physiological and developmental functions in a spatiotemporal manner. Biosynthesis of PGs is often blocked with the aid of nonspecific agents such as chlorate, a bleaching agent, and brefeldin A, a fungal metabolite, to elucidate the biological roles of GAG chains. Unfortunately, these agents are highly lethal to model organisms. Xylosides are known to prime GAG chains. Therefore, we hypothesized that modified xylose analogs may able to inhibit the biosynthesis of PGs. To test this, we synthesized a library of novel 4-deoxy-4-fluoroxylosides with various aglycones using click chemistry and examined each for its ability to inhibit heparan sulfate and chondroitin sulfate using Chinese hamster ovary cells as a model cellular system.

Received for publication, July 31, 2008

^* This work was supported, by National Institutes of Health Grant GM075168 (to B. K.). This work was also supported by the Human Frontiers Science Program (to B. K.) and by a grant-in-aid for science research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

¹ Both authors contributed equally to this work.

² Visiting Graduate Fellow from the Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112.

³ To whom correspondence should be addressed: Dept. of Medicinal Chemistry, Skaggs Hall, Rm. 307, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112. Tel.: 801-587-9474; Fax: 801-585-9119; E-mail: KUBY{at}pharm.utah.edu.

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