title: 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.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Williams
authors.affiliation: Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sami
authors.initials: S
authors.lastname: Caner
authors.affiliation: Genome Sciences and Technology Graduate Programme, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Tysoe
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nham T
authors.initials: NT
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wicki
authors.affiliation: 1] Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada. [2] Department of Earth, Ocean and Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: Centre for Drug Research and Development, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Coleman
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: McNeill
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Violet
authors.initials: V
authors.lastname: Yuen
authors.affiliation: 1] Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada. [2] Department of Earth, Ocean and Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. [2] Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Brayer
mesh_terms: D001665:Binding Sites; D002109:Caffeic Acids / Q000737:chemistry; D002240:Carbohydrate Sequence; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D047309:Flavones / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry; D044948:Flavonols / Q000737:chemistry*; D015870:Gene Expression; D006027:Glycosides / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D014312:Trisaccharides / Q000737:chemistry; D000516:alpha-Amylases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics
chemical_list: D002109:Caffeic Acids; D004791:Enzyme Inhibitors; D047309:Flavones; D005419:Flavonoids; D044948:Flavonols; D006027:Glycosides; D008024:Ligands; D011994:Recombinant Proteins; D014312:Trisaccharides; C000611831:montbretin A; C040015:myricetin; D000516:alpha-Amylases; C040048:caffeic acid