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Title: Potent human α-amylase inhibition by the β-defensin-like protein helianthamide

Here, 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 (K i = 10 pM) peptidic HPA inhibitor, helianthamide, from the Caribbean sea anemone Stichodactyla helianthus. Active helianthamide was produced in Escherichia coli via 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:
 [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [1] ;  [1] ;  [2] ;  [2] ;  [3]
  1. Michael Smith Lab., Vancouver, BC (Canada)
  2. Univ. of British Columbia, Vancouver, BC (Canada)
  3. Michael Smith Lab., Vancouver, BC (Canada); Univ. of British Columbia, Vancouver, BC (Canada)
Publication Date:
Grant/Contract Number:
111082; AC02-76SF00515; P41GM103393
Type:
Published Article
Journal Name:
ACS Central Science
Additional Journal Information:
Journal Volume: 2; Journal Issue: 3; Journal ID: ISSN 2374-7943
Publisher:
American Chemical Society (ACS)
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1239610
Alternate Identifier(s):
OSTI ID: 1244269

Tysoe, Christina, Williams, Leslie K., Keyzers, Robert, Nguyen, Nham T., Tarling, Chris, Wicki, Jacqueline, Goddard-Borger, Ethan D., Aguda, Adeleke H., Perry, Suzanne, Foster, Leonard J., Andersen, Raymond J., Brayer, Gary D., and Withers, Stephen G.. Potent human α-amylase inhibition by the β-defensin-like protein helianthamide. United States: N. p., Web. doi:10.1021/acscentsci.5b00399.
Tysoe, Christina, Williams, Leslie K., Keyzers, Robert, Nguyen, Nham T., Tarling, Chris, Wicki, Jacqueline, Goddard-Borger, Ethan D., Aguda, Adeleke H., Perry, Suzanne, Foster, Leonard J., Andersen, Raymond J., Brayer, Gary D., & Withers, Stephen G.. Potent human α-amylase inhibition by the β-defensin-like protein helianthamide. United States. doi:10.1021/acscentsci.5b00399.
Tysoe, Christina, Williams, Leslie K., Keyzers, Robert, Nguyen, Nham T., Tarling, Chris, Wicki, Jacqueline, Goddard-Borger, Ethan D., Aguda, Adeleke H., Perry, Suzanne, Foster, Leonard J., Andersen, Raymond J., Brayer, Gary D., and Withers, Stephen G.. 2016. "Potent human α-amylase inhibition by the β-defensin-like protein helianthamide". United States. doi:10.1021/acscentsci.5b00399.
@article{osti_1239610,
title = {Potent human α-amylase inhibition by the β-defensin-like protein helianthamide},
author = {Tysoe, Christina and Williams, Leslie K. and Keyzers, Robert and Nguyen, Nham T. and Tarling, Chris and Wicki, Jacqueline and Goddard-Borger, Ethan D. and Aguda, Adeleke H. and Perry, Suzanne and Foster, Leonard J. and Andersen, Raymond J. and Brayer, Gary D. and Withers, Stephen G.},
abstractNote = {Here, 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 anemone Stichodactyla helianthus. Active helianthamide was produced in Escherichia coli via 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.},
doi = {10.1021/acscentsci.5b00399},
journal = {ACS Central Science},
number = 3,
volume = 2,
place = {United States},
year = {2016},
month = {2}
}