Mechanism-Based Probing, Characterization, and Inhibitor Design of Glycosidases and Glycosyltransferases

被引:15
作者
Hinou, Hiroshi [1 ,2 ,3 ]
Nishimura, Shin-Ichiro [1 ,2 ,3 ]
机构
[1] Hokkaido Univ, Grad Sch Adv Life Sci, Sapporo, Hokkaido 0010021, Japan
[2] Hokkaido Univ, Frontier Res Ctr Post Genome Sci & Technol, Sapporo, Hokkaido 0010021, Japan
[3] Natl Inst Adv Ind Sci & Technol, Drug Seeds Discovery Res Lab, Toyohira Ku, Sapporo, Hokkaido 0628517, Japan
关键词
VIBRIO-CHOLERAE NEURAMINIDASE; RESONANCE ENERGY-TRANSFER; INDUCED CONFORMATIONAL-CHANGE; CRYSTAL-STRUCTURE; CERAMIDE GLYCANASE; TRIANTENNARY GLYCOPEPTIDE; STRUCTURAL-ANALYSIS; BISUBSTRATE ANALOG; CATALYTIC DOMAIN; RATIONAL DESIGN;
D O I
10.2174/156802609787354298
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Recent structural and kinetic studies indicated that enzymes shift their peripheral structures of the catalytic sites dynamically to modify the substrate structures. Molecules which disturb such mechanism of specific enzymes may become potent candidates for therapeutic reagent. This article describes a versatile strategy to synthesize new class of mechanism-based inhibitors for glycosyltransferases and glycoside hydrolases. Combination of irreversible tagging and proteomic analysis of crucial amino acid residues using MALDI-TOF/TOF mass spectrometry allowed a promising method to probe such invisible transitional state in the enzymatic reactions. Feasibility of the fluorescence energy resonance transfer (FRET) is also documented as novel protocol for the real-time and continuous monitoring of glycosyltransferase catalyzed reactions. It was demonstrated that FRET method greatly facilitates discovery research of selective inhibitors in combination with click chemistry.
引用
收藏
页码:106 / 116
页数:11
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