Portal de Periódicos da CAPES

Crystallographic Studies on α- and β-D-glucopyranosyl Formamide Analogues, Inhibitors of Glycogen Phosphorylase

2003; Taylor & Francis; Volume: 21; Issue: 4-5 Linguagem: Inglês

10.1080/10242420310001614360

1029-2446

Evangelia D. Chrysina, Nikos G. Oikonomakos, S.E. Zographos, Magda Kosmopoulou, Nicolas Bischler, D.D. Leonidas, László Kovács, Tibor Docsa, Pál Gergely, László Somsák,

Biochemical and Molecular Research

AbstractThe catalytic site of glycogen phosphorylase (GP) is currently under investigation as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Three D-glucopyranosyl analogues, C-(1-azido-α-D-glucopyranosyl) formamide, C-(1-acetamido-α-D-glucopyranosyl) formamide, and C-(1-hydroxy-β-D-glucopyranosyl) formamide, were recognised as moderate competitive inhibitors of muscle glycogen phosphorylase b (GPb) [with respect to α-D-glucose 1-phosphate (Glc-1-P)] with Ki values of 1.80 (±0.2) mM, 0.31 (±0.01) mM, and 0.88 (±0.04) mM, respectively. In order to elucidate the structural basis of inhibition, we determined the structure of muscle GPb complexed with the three compounds at 2.1, 2.06 and 2.0 A resolution, respectively. The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalisation for understanding potency of the inhibitors. The glucopyranose moiety m...