Yurong Chen, Adrianus M C H van den Nieuwendijk, Liang Wu, Elisha Moran, Foteini Skoulikopoulou, Vera van Riet, Hermen S Overkleeft, Gideon J Davies, Zachary Armstrong
Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, β- d -glucuronidases, and N -acetyl-glucosaminidases. The mode of inhibition of glucuronidases, in contrast to sialidases, has long been enigmatic as siastatin B appears too bulky and incorrectly substituted to be accommodated within a β- d -glucuronidase active site pocket. Herein, we show through crystallographic analysis of protein-inhibitor complexes that siastatin B generates both a hemiaminal and a 3-geminal diol iminosugar (3-GDI) that are, rather than the parent compound, directly responsible for enzyme inhibition...
December 20, 2023: Journal of the American Chemical Society