The amylase inhibitor montbretin A reveals a new glycosidase inhibition motif.

Abstract

The complex plant flavonol glycoside montbretin A is a potent (Ki = 8 nM) and specific inhibitor of human pancreatic α-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 α-amylase complex confirmed the importance of this core structure and revealed a novel mode of glycosidase inhibition wherein internal π-stacking interactions between the myricetin and caffeic acid organize their ring hydroxyls for optimal hydrogen bonding to the α-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.

• Authors: Leslie K Williams, Xiaohua Zhang, Sami Caner, Christina Tysoe, Nham T Nguyen, Jacqueline Wicki, David E Williams, John Coleman, John H McNeill, Violet Yuen, Raymond J Andersen, Stephen G Withers, Gary D Brayer
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 11 Issue 9 Pg. 691-6 (Sep 2015) ISSN: 1552-4469 [Electronic] United States
• PMID: 26214255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Caffeic Acids
• Enzyme Inhibitors
• Flavones
• Flavonoids
• Flavonols
• Glycosides
• Ligands
• Recombinant Proteins
• Trisaccharides
• montbretin A
• myricetin
• alpha-Amylases
• caffeic acid

Topics

• Binding Sites
• Caffeic Acids (chemistry)
• Carbohydrate Sequence
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry)
• Flavones (chemistry)
• Flavonoids (chemistry)
• Flavonols (chemistry)
• Gene Expression
• Glycosides (chemistry)
• Humans
• Hydrogen Bonding
• Hydrolysis
• Ligands
• Models, Molecular
• Molecular Sequence Data
• Pichia (genetics, metabolism)
• Protein Binding
• Recombinant Proteins (chemistry, genetics)
• Trisaccharides (chemistry)
• alpha-Amylases (antagonists & inhibitors, chemistry, genetics)