Potent Human α-Amylase Inhibition by the β-Defensin-like Protein Helianthamide

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.

doi:10.1021/acscentsci.5b00399

Title: Potent Human α-Amylase Inhibition by the β-Defensin-like Protein Helianthamide

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Abstract

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:

Tysoe, Christina ^[1]; Williams, Leslie K. ^[2]; Keyzers, Robert ^[3]; Nguyen, Nham T. ^[2]; Tarling, Chris ^[4]; Wicki, Jacqueline ^[4]; Goddard-Borger, Ethan D. ^[4]; Aguda, Adeleke H. ^[2]; Perry, Suzanne ^[1]; Foster, Leonard J. ^[1]; Andersen, Raymond J. ^[3]; Brayer, Gary D. ^[2]; Withers, Stephen G. ^[5]

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, Department of Earth and Ocean Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
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

Publication Date:: Fri Feb 26 00:00:00 EST 2016

Research Org.:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:: 1239610

Alternate Identifier(s):: OSTI ID: 1244269

Grant/Contract Number:: AC02-76SF00515; 111082; P41GM103393

Resource Type:: Published Article

Journal Name:: ACS Central Science

Additional Journal Information:: Journal Name: ACS Central Science Journal Volume: 2 Journal Issue: 3; Journal ID: ISSN 2374-7943

Publisher:: American Chemical Society

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    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., 2016. 
Web.  doi:10.1021/acscentsci.5b00399.

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                    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.  https://doi.org/10.1021/acscentsci.5b00399

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                    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. Fri .  
"Potent Human α-Amylase Inhibition by the β-Defensin-like Protein Helianthamide".  United States.  https://doi.org/10.1021/acscentsci.5b00399.

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@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         = {Fri Feb 26 00:00:00 EST 2016},

  month        = {Fri Feb 26 00:00:00 EST 2016}

}

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