Selective inhibition of β-1,4- and α-1,3-galactosyltransferases: donor sugar-nucleotide based approach

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• 作者：Takayama ; Shuichi ; Chung ; Sang J. ; Igarashi ; Yasuhiro ; Ichikawa ; Yoshitaka ; Sepp ; Armin ; Lechler ; Robert I. ; et. al.
• 关键词：Carbohydrates ; enzyme inhibitors ; glycosylation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1999
• 出版时间：February, 1999
• 年：1999
• 卷：7
• 期：2
• 页码：401-409
• 全文大小：337 K

文摘

A combined rational and library approach was used to identify bisphosphonates (IC₅₀=20 μM) and galactose type 1-N-iminosugar (IC₅₀=45 μM) as novel motifs for selective inhibition of β-1,4-galactosyltransferase (β-1,4-GalT) and α-1,3-galactosyltransferase (α-1,3-GalT), respectively. Our results demonstrate that, though these two galactosyltransferases both utilize the same donor sugar-nucleotide (UDP-Gal), the difference in their mechanisms can be utilized to design donor sugar or nucleotide analogues with inhibitory activities selective for only one of the galactosyltransferases. Investigation of β-1,4-GalT inhibition using UDP-2-deoxy-2-fluorogalactose (UDP-2-F-Gal), UDP, and bisphosphonates, also led to the observation of metal dependent inhibition of β-1,4-GalT. These observations and the novel inhibitor motifs identified in this study pave the way for the design and identification of even more potent and selective galactosyltransferase inhibitors. ©