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J. Biol. Chem., Vol. 280, Issue 52, 42817-42825, December 30, 2005

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Enzymatic Redesigning of Biologically Active Heparan Sulfate^*

Jinghua Chen1, Fikri Y. Avci, Eva M. Muñoz, Lynda M. McDowell¶, Miao Chen, Lars C. Pedersen||, Lijuan Zhang¶, Robert J. Linhardt, and Jian Liu2

From the Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, the Department of Chemistry and Chemical Biology, Biology and Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, the ^¶Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, and the ^||Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Heparan sulfate carries a wide range of biological activities, regulating blood coagulation, cell differentiation, and inflammatory responses. The sulfation patterns of the polysaccharide are essential for the biological activities. In this study, we report an enzymatic method for the sulfation of multimilligram amounts of heparan sulfate with specific functions using immobilized sulfotransferases combined with a 3'-phosphoadenosine 5'-phosphosulfate regeneration system. By selecting appropriate enzymatic modification steps, an inactive precursor has been converted to the heparan sulfate having three distinct biological activities, associated with binding to antithrombin, fibroblast growth factor-2, and herpes simplex virus envelope glycoprotein D. Because the recombinant sulfotransferases are expressed in bacteria, and the method uses a low cost sulfo donor, it can be readily utilized to synthesize large quantities of anticoagulant heparin drug or other biologically active heparan sulfates.

Received for publication, April 20, 2005 , and in revised form, September 28, 2005.

^* This work is supported in part by National Institutes of Health Grants AI50050 (to J. L.), HL52622 and GM38060 (to R. J. L.), and GM069968 (to L. Z.) and American Heart Association, Mid-Atlantic Affiliate, Grant-in-Aid 0355800U (to J. L.). 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 Present address: College of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, Hubei, China.

² To whom correspondence should be addressed: Rm. 309, Beard Hall, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-843-6511; Fax: 919-843-5432; E-mail: jian_liu{at}unc.edu.

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