|Title||The amylase inhibitor montbretin A reveals a new glycosidase inhibition motif|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Williams, LK, Zhang, X, Caner, S, Tysoe, C, Nguyen, NT, Wicki, J, Williams, DE, Coleman, J, McNeill, JH, Yuen, V, Andersen, RJ, Withers, SG, Brayer, GD|
|Journal||NATURE CHEMICAL BIOLOGY|
The complex plant flavonol glycoside montbretin A is a potent (K-i = 8 nM) and specific inhibitor of human pancreatic alpha-amylase with potential as a therapeutic for diabetes and obesity. Controlled degradation studies on montbretin A, coupled with inhibition analyses, identified an essential high-affinity core structure comprising the myricetin and caffeic acid moieties linked via a disaccharide. X-ray structural analyses of the montbretin A-human alpha-amylase complex confirmed the importance of this core structure and revealed a novel mode of glycosidase inhibition wherein internal pi-stacking interactions between the myricetin and caffeic acid organize their ring hydroxyls for optimal hydrogen bonding to the alpha-amylase catalytic residues D197 and E233. This novel inhibitory motif can be reproduced in a greatly simplified analog, offering potential for new strategies for glycosidase inhibition and therapeutic development.