Crystallographic analysis of the interactions of Drosophila melanogaster Golgi α-mannosidase II with the naturally occurring glycomimetic salacinol and its analogues

Golgi alpha-mannosidase II, a component of the N-glycosylation pathway and a member of glycosyl hydrolase family 38, is an attractive target for inhibition with anti-tumor or anti-inflammatory outcomes. This enzyme operates via the classical two-step catalytic mechanism of retaining glycosidases. Recently, a novel, general class of glycosidase inhibitors has been developed based on the natural anti-diabetic compound, salacinol. Previously, these inhibitors have shown activity against intestinal alpha-glucosidases. glucoamylase, and alpha-amylase. Herein, we investigate by X-ray crystallography. the interactions of these compounds with Golgi alpha-mannosidase II, and compare these interactions with those of the naturally occurring inhibitor. swainsonine. The mode of interaction of analogues of salacinol to alpha-mannosidase II is distinct from that described previously for glucosidases. The results demonstrate the ability of these general glycosidase inhibitors to interact with enzymes of a wide range of structures, and shed light on the general binding properties of alpha-mannosidase II. Specifically, they highlight the importance of octahedral coordination to the active site zinc atom for good inhibition, and the ability of even these weak inhibitors to form critical interactions with active site carboxylates and, by virtue of their permanent positive charge, to simulate the oxacarbenium nature of the transition state. (C) 2004 Elsevier Ltd. All rights reserved.