Small molecule inhibitors of mucin-type O-linked glycosylation from a uridine-based library

被引:53
作者
Hang, HC
Yu, C
Ten Hagen, KG
Tian, E
Winans, KA
Tabak, LA
Bertozzi, CR [1 ]
机构
[1] Univ Calif Berkeley, Ctr New Direct Organ Synth, Dept Chem, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Ctr New Direct Organ Synth, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[3] Univ Calif Berkeley, Ctr New Direct Organ Synth, Howard Hughes Med Inst, Berkeley, CA 94720 USA
[4] NIDDK, Sect Biol Chem, NIH, Bethesda, MD USA
来源
CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 03期
关键词
D O I
10.1016/j.chembiol.2004.02.023
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The polypeptide N-acetyl-alpha-galactosaminyltransferases (ppGalNAcTs, also abbreviated ppGaNTases) initiate mucin-type O-linked glycosylation and therefore play pivotal roles in cell-cell communication and protection of tissues. In order to develop new tools for studying mucin-type O-linked glycosylation, we screened a 1338 member uridine-based library to identify small molecule inhibitors of ppGalNAcTs. Using a high-throughput enzyme-linked lectin assay (ELLA), two inhibitors of murine ppGalNAcT-1 (K-I similar to 8 muM) were identified that also inhibit several other members of the family. The compounds did not inhibit other mammalian glycosyltransferases or nucleotide sugar utilizing enzymes, suggesting selectivity for the ppGalNAcTs. Treatment of cells with the compounds abrogated mucin-type O-linked glycosylation but not N-linked glycosylation and also induced apoptosis. These uridine analogs represent the first generation of chemical tools to study the functions of mucin-type O-linked glycosylation.
引用
收藏
页码:337 / 345
页数:9
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