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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites
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Caffeic Acids / chemistry
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Carbohydrate Sequence
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Drug Design*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Flavones / chemistry
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Flavonoids / chemistry
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Flavonols / chemistry*
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Gene Expression
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Glycosides / chemistry*
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Humans
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Hydrogen Bonding
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Hydrolysis
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Ligands
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Models, Molecular
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Molecular Sequence Data
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Pichia / genetics
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Pichia / metabolism
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Protein Binding
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Trisaccharides / chemistry
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alpha-Amylases / antagonists & inhibitors
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alpha-Amylases / chemistry*
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alpha-Amylases / genetics
Substances
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Caffeic Acids
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Enzyme Inhibitors
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Flavones
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Flavonoids
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Flavonols
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Glycosides
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Ligands
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Recombinant Proteins
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Trisaccharides
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montbretin A
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myricetin
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alpha-Amylases
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caffeic acid
Associated data
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PDB/4W93
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PubChem-Substance/251974350
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PubChem-Substance/251974351
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PubChem-Substance/251974352
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PubChem-Substance/251974353
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PubChem-Substance/251974354
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PubChem-Substance/251974355
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PubChem-Substance/251974356
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PubChem-Substance/251974357
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PubChem-Substance/251974358
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PubChem-Substance/251974359
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PubChem-Substance/251974360
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PubChem-Substance/251974361
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PubChem-Substance/251974362
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PubChem-Substance/251974363