The amylase inhibitor montbretin A reveals a new glycosidase inhibition motif

Nat Chem Biol. 2015 Sep;11(9):691-6. doi: 10.1038/nchembio.1865. Epub 2015 Jul 27.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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

Associated data

  • PDB/4W93
  • PubChem-Substance/251974350
  • PubChem-Substance/251974351
  • PubChem-Substance/251974352
  • PubChem-Substance/251974353
  • PubChem-Substance/251974354
  • PubChem-Substance/251974355
  • PubChem-Substance/251974356
  • PubChem-Substance/251974357
  • PubChem-Substance/251974358
  • PubChem-Substance/251974359
  • PubChem-Substance/251974360
  • PubChem-Substance/251974361
  • PubChem-Substance/251974362
  • PubChem-Substance/251974363