A common sugar-nucleotide-mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F-GalNAc (Ac3).
A common sugar-nucleotide-mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F-GalNAc (Ac3).
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6F-GalNAc (Ac3) 证明了一种常见的糖核苷酸介导的（糖胺）聚糖生物合成抑制机制。
DOI：
10.1096/fj.14-264226
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
vanKuppevelt,ToinH
中科院分区：
文献类型：
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作者：
vanWijk,XanderM;Lawrence,Roger;Thijssen,VictorL;vandenBroek,SebastiaanA;Troost,Ran;vanScherpenzeel,Monique;Naidu,Natasha;Oosterhof,Arie;Griffioen,ArjanW;Lefeber,DirkJ;vanDelft,FlorisL;vanKuppevelt,ToinH
糖胺聚糖 (GAG) 多糖与多种细胞过程有关，其数量和结构的改变与癌症等疾病有关。在这项研究中，我们探讨了 11 种糖类似物干扰 GAG 生物合成的能力。选择一种类似物，其修饰不直接参与糖苷键形成，即 6F-N-乙酰基-d-半乳糖胺 (GalNAc) (Ac3)，用于进一步研究其代谢和生物学效应。用 50 μM 6F-GalNAc (Ac3) 处理人卵巢癌细胞可抑制 GAG（硫酸软骨素/硫酸皮肤素约 50-60%，硫酸乙酰肝素约 35%）、N-乙酰基-d-葡萄糖胺 (GlcNAc)/GalNAc 的生物合成，其中含有被凝集素曼陀罗和花生凝集素识别的聚糖（约 74 和∼43%，分别）和O-GlcNAc蛋白修饰。就功能而言，6F-GalNAc (Ac3) 治疗可抑制生长因子信号传导并将体内血管生成减少约 33%。尽管该类似物很容易在细胞中转化为尿苷 5'-二磷酸 (UDP) 激活形式，但它并未掺入 GAG 中。相反，它大大减少了细胞的 UDP-GalNAc 和 UDP-GlcNAc 池。结合文献数据，这些发现表明，不掺入的核苷酸糖消耗是糖类似物抑制 GAG/聚糖生物合成的常见机制。-Van Wijk, X. M., Lawrence, R., Thijssen, V. L., van den Broek, S. A., Troost, R., van Scherpenzeel, M., Naidu, N., Oosterhof, A., Griffioen, A. W.，Lefeber，D. J.，van Delft，F. L.，van Kuppevelt，T. H. 一种常见的糖核苷酸介导的（糖氨基）聚糖生物合成抑制机制，如 6F-GalNAc (Ac3) 所证明的。
Glycosaminoglycan (GAG) polysaccharides have been implicated in a variety of cellular processes, and alterations in their amount and structure have been associated with diseases such as cancer. In this study, we probed 11 sugar analogs for their capacity to interfere with GAG biosynthesis. One analog, with a modification not directly involved in the glycosidic bond formation, 6F-N-acetyl-d-galactosamine (GalNAc) (Ac3), was selected for further study on its metabolic and biologic effect. Treatment of human ovarian carcinoma cells with 50 μM 6F-GalNAc (Ac3) inhibited biosynthesis of GAGs (chondroitin/dermatan sulfate by ∼50–60%, heparan sulfate by ∼35%), N-acetyl-d-glucosamine (GlcNAc)/GalNAc containing glycans recognized by the lectins Datura stramonium and peanut agglutinin (by ∼74 and ∼43%, respectively), and O-GlcNAc protein modification. With respect to function, 6F-GalNAc (Ac3) treatment inhibited growth factor signaling and reduced in vivo angiogenesis by ∼33%. Although the analog was readily transformed in cells into the uridine 5′-diphosphate (UDP)-activated form, it was not incorporated into GAGs. Rather, it strongly reduced cellular UDP-GalNAc and UDP-GlcNAc pools. Together with data from the literature, these findings indicate that nucleotide sugar depletion without incorporation is a common mechanism of sugar analogs for inhibiting GAG/glycan biosynthesis.—Van Wijk, X. M., Lawrence, R., Thijssen, V. L., van den Broek, S. A., Troost, R., van Scherpenzeel, M., Naidu, N., Oosterhof, A., Griffioen, A. W., Lefeber, D. J., van Delft, F. L., van Kuppevelt, T. H. A common sugar-nucleotide-mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F-GalNAc (Ac3).