title: Potent Human α-Amylase Inhibition by the β-Defensin-like Protein Helianthamide.
abstract: Selective inhibitors of human pancreatic α-amylase (HPA) are an effective means of controlling blood sugar levels in the management of diabetes. A high-throughput screen of marine natural product extracts led to the identification of a potent (Ki= 10 pM) peptidic HPA inhibitor, helianthamide, from the Caribbean sea anemoneStichodactyla helianthus.Active helianthamide was produced inEscherichia colivia secretion as a barnase fusion protein. X-ray crystallographic analysis of the complex of helianthamide with porcine pancreatic α-amylase revealed that helianthamide adopts a β-defensin fold and binds into and across the amylase active site, utilizing a contiguous YIYH inhibitory motif. Helianthamide represents the first of a novel class of glycosidase inhibitors and provides an unusual example of functional malleability of the β-defensin fold, which is rarely seen outside of its traditional role in antimicrobial peptides.
authors.affiliation: Centre for High-Throughput Biology, Michael Smith Laboratories , 185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Tysoe
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Williams
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada; Department of Earth and Ocean Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Keyzers
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Nham T
authors.initials: NT
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Tarling
authors.affiliation: Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wicki
authors.affiliation: Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Goddard-Borger
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Adeleke H
authors.initials: AH
authors.lastname: Aguda
authors.affiliation: Centre for High-Throughput Biology, Michael Smith Laboratories , 185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Perry
authors.affiliation: Centre for High-Throughput Biology, Michael Smith Laboratories , 185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Foster
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada; Department of Earth and Ocean Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Brayer
authors.affiliation: Centre for High-Throughput Biology, Michael Smith Laboratories, 185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers