623114-67-0Relevant academic research and scientific papers
Probing the substrate specificity of golgi α-mannosidase II by use of synthetic oligosaccharides and a catalytic nucleophile mutant
Zhong, Wei,Kuntz, Douglas A.,Ember, Brian,Singh, Harminder,Moremen, Kelley W.,Rose, David R.,Boons, Geert-Jan
supporting information; experimental part, p. 8975 - 8983 (2009/02/03)
Inhibition of Golgi α-mannosidase II (GMII), which acts late in the N-glycan processing pathway, provides a route to blocking cancer-induced changes in cell surface oligosaccharide structures. To probe the substrate requirements of GMII, oligosaccharides were synthesized that contained an α(1,3)- or α(1,6)-linked 1-thiomannoside. Surprisingly, these oligosaccharides were not observed in X-ray crystal structures of native Drosophila GMII (dGMII). However, a mutant enzyme in which the catalytic nucleophilic aspartate was changed to alanine (D204A) allowed visualization of soaked oligosaccharides and led to the identification of the binding site for the α(1,3)-linked mannoside of the natural substrate. These studies also indicate that the conformational change of the bound mannoside to a high-energy B2,5 conformation is facilitated by steric hindrance from, and the formation of strong hydrogen bonds to, Asp204. The observation that 1-thio-linked mannosides are not well tolerated by the catalytic site of dGMII led to the synthesis of a pentasaccharide containing the α(1,6)-linked Man of the natural substrate and the β(1,2)-linked GlcNAc moiety proposed to be accommodated by the extended binding site of the enzyme. A cocrystal structure of this compound with the D204A enzyme revealed the molecular interactions with the β(1,2)-linked GlcNAc. The structure is consistent with the ～80-fold preference of dGMII for the cleavage of substrates containing a nonreducing β(1,2)-linked GlcNAc. By contrast, the lysosomal mannosidase lacks an equivalent GlcNAc binding site and kinetic analysis indicates oligomannoside substrates without non-reducing-terminal GlcNAc modifications are preferred, suggesting that selective inhibitors for GMII could exploit the additional binding specificity of the GlcNAc binding site.
Synthetic study on Campylobacter jejuni lipopolysaccharides: An improved synthesis of a branched, heptose-containing trisaccharide core structure and its conversion into ganglioside GD3 related hexasaccharide
Hori, Koji,Sawada, Naoki,Ando, Hiromune,Ishida, Hideharu,Kiso, Makoto
, p. 3752 - 3760 (2007/10/03)
The first synthesis of the oligosaccharide skeleton of the Campylobacter jejuni lipooligosaccharide composed of a branched, heptose-containing trisaccharide core structure and, including a substantially improved preparation of the core structure, the ganglioside GD3 related trisaccharide epitope is reported. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
