Naphthyl Thio- and Carba-xylopyranosides for Exploration of the Active Site of [beta]-1,4-Galactosyltransferase 7 ([beta]4GalT7)

Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for [beta]-1,4-galactosyltransferase7 ([beta]4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for [beta]4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba-[beta]-xylopyranoside in the d-configuration proved to be a good substrate for [beta]4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues. Favorable π-π interactions between the 2-naphthyl moiety and a tyrosine side chain of the enzyme were observed for the thio analogues, which open up for the design of efficient GAG primers and inhibitors.