Synthesis of N-glycan units for assessment of substrate structural requirements of N-acetylglucosaminyltransferase III
Synthesis of N-glycan units for assessment of substrate structural requirements of N-acetylglucosaminyltransferase III
复制标题
DOI：
10.1016/j.bmcl.2014.07.074
复制
发表时间：
2014-09-15
影响因子：
2.7
通讯作者：
Yamaguchi, Yoshiki
中科院分区：
文献类型：
--
作者：
Hanashima, Shinya;Korekane, Hiroaki;Yamaguchi, Yoshiki
N-乙酰葡糖胺转移酶（GnT）III是一种糖基转移酶，通过将GlcNAc转移到核心甘露糖的4位来产生二分型N-聚糖。二分型N-聚糖通过其载体蛋白的功能调节参与生理和病理过程。通过使用GnT-III的特异性抑制剂，将大大加快对二分聚糖生物学功能的理解。然而，到目前为止，这种抑制剂尚未开发，甚至GnT-III的底物结合模式也没有完全理解。为了深入了解底物所需的结构特征，我们系统地合成了四个N-聚糖单元，即平分和非平分N-聚糖的分支部分。这一系列的合成是从一个共同的核心三甘露糖，得到平分的四糖和六糖以及非平分的三糖和五糖。使用合成底物的竞争性GnT-III抑制试验显示Man β（1-4）GlcNAc部分的重要作用。与先前的报道一致，α 1，3-分支上的GlcNAc也参与相互作用。本研究阐明的GnT-III的结构要求将为合理的抑制剂设计提供基础。(C)2014爱思唯尔有限公司版权所有。
N-Acetylglucosaminyltransferase (GnT) III is a glycosyltransferase which produces bisected N-glycans by transferring GlcNAc to the 4-position of core mannose. Bisected N-glycans are involved in physiological and pathological processes through the functional regulation of their carrier proteins. An understanding of the biological functions of bisected glycans will be greatly accelerated by use of specific inhibitors of GnT-III. Thus far, however, such inhibitors have not been developed and even the substrate-binding mode of GnT-III is not fully understood. To gain insight into structural features required of the substrate, we systematically synthesized four N-glycan units, the branching parts of the bisected and non-bisected N-glycans. The series of syntheses were achieved from a common core trimannose, giving bisected tetra-and hexasaccharides as well as non-bisected tri- and pentasaccharides. A competitive GnT-III inhibition assay using the synthetic substrates revealed a vital role for the Man beta(1-4) GlcNAc moiety. In keeping with previous reports, GlcNAc at the alpha 1,3-branch is also involved in the interaction. The structural requirements of GnT-III elucidated in this study will provide a basis for rational inhibitor design. (C) 2014 Elsevier Ltd. All rights reserved.