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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dissecting the substrate recognition of 3-O-sulfotransferase for the biosynthesis of anticoagulant heparin
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Dissecting the substrate recognition of 3-O-sulfotransferase for the biosynthesis of anticoagulant heparin

机译：剖析3-O-磺基转移酶用于抗凝肝素生物合成的底物识别

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摘要

Heparin is a polysaccharide-based natural product that is used clinically as an anticoagulant drug. Heparan sulfate 3-O-sulfotransferase (3-OST) is an enzyme that transfers a sulfo group to the 3-OH position of a glucosamine unit. 3-OST is present in multiple isoforms, and the polysaccharides modified by these different isoforms perform distinct biological functions. 3-OST isoform 1 (3-OST-1) is the key enzyme for the biosynthesis of anticoagulant heparin. Here, we report the crystal structure of the ternary complex of 3-OST-1,3'-phosphoadenosine 5-phosphate, and a heptasaccharide substrate. Comparisons to previously determined structures of 3-OST-3 reveal unique binding modes used by the different isoforms of 3-OST for distinguishing the fine structures of saccharide substrates. Our data demonstrate that the saccharide substrates display distinct conformations when interacting with the different 3-OST isoforms. Sitedirected mutagenesis data suggest that several key amino residues, including Lys259, Thr256, and Trp283 in 3-OST-3 and Arg268 in 3-OST-1, play important roles in substrate binding and specificity between isoforms. These results deepen our understanding of the biosynthetic mechanism of heparan sulfate and provide structural information for engineering enzymes for an enhanced biosynthetic approach to heparin production.
机译：肝素是一种基于多糖的天然产物，在临床上被用作抗凝药物。硫酸乙酰肝素3-O-磺基转移酶（3-OST）是一种将磺基转移至葡萄糖胺单元的3-OH位置的酶。 3-OST存在多种同工型，被这些不同同工型修饰的多糖具有不同的生物学功能。 3-OST同工型1（3-OST-1）是抗凝肝素生物合成的关键酶。在这里，我们报告了3-OST-1,3'-磷酸腺苷5-磷酸和七糖底物的三元复合物的晶体结构。与先前确定的3-OST-3结构的比较揭示了3-OST不同同工型用于区分糖类底物精细结构的独特结合模式。我们的数据表明，糖底物在与不同的3-OST同工型相互作用时显示出不同的构象。定点诱变数据表明，几个关键的氨基残基，包括3-OST-3中的Lys259，Thr256和Trp283，以及3-OST-1中的Arg268，在底物结合和同工型之间的特异性中起重要作用。这些结果加深了我们对硫酸乙酰肝素的生物合成机理的理解，并为工程酶提供了结构信息，以增强肝素生产的生物合成方法。

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    Andrea F. Moon; Yongmei Xu; Susan M. Woody; Joseph M. Krahn; Robert J. Linhardt; Jian Liu; Lars C. Pedersen;

  • 作者单位

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;

    Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;

    Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;

    Departmeni of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180;

    Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    oligosaccharides; substrate specificity; ternary complex; heparan sulfate;

    机译：寡糖;底物特异性三元复合体硫酸乙酰肝素;

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