Garud Dinesh R, Tran Vy M, Victor Xylophone V, Koketsu Mamoru, Kuberan Balagurunathan
Department of Chemistry, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
J Biol Chem. 2008 Oct 24;283(43):28881-7. doi: 10.1074/jbc.M805939200. Epub 2008 Aug 14.
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.
蛋白聚糖（PGs）由一个蛋白质部分和一个复杂的糖胺聚糖（GAG）多糖部分组成。GAG链负责多种生物学活性。GAG链共价连接到核心蛋白的丝氨酸残基上。PG生物合成的第一步是核心蛋白某些丝氨酸残基的木糖基化。然后组装一个特定的连接四糖，并作为GAG链延长的受体。如果内源性GAG链的产生被选择性抑制，就可以以时空方式确定这些内源性分子在生理和发育功能中的作用。PG的生物合成通常借助非特异性试剂如氯酸盐（一种漂白剂）和布雷菲德菌素A（一种真菌代谢物）来阻断，以阐明GAG链的生物学作用。不幸的是，这些试剂对模式生物具有高度致死性。已知木糖苷可引发GAG链。因此，我们假设修饰的木糖类似物可能能够抑制PG的生物合成。为了验证这一点，我们使用点击化学合成了一系列带有各种糖苷配基的新型4-脱氧-4-氟木糖苷库，并以中国仓鼠卵巢细胞作为模型细胞系统，检测了每种化合物抑制硫酸乙酰肝素和硫酸软骨素的能力。
