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

TitlePotent Human α-Amylase Inhibition by the β-Defensin-like Protein Helianthamide
Publication TypeJournal Article
Year of Publication2016
AuthorsTysoe, C, Williams, LK, Keyzers, R, Nguyen, NT, Tarling, C, Wicki, J, Goddard-Borger, ED, Aguda, AH, Perry, S, Foster, LJ, Andersen, RJ, Brayer, GD, Withers, SG
JournalACS Central Science

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.