Potent Human ?-Amylase Inhibition by the ?-Defensin-like Protein Helianthamide.

ABSTRACT: Selective inhibitors of human pancreatic ?-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 ?-amylase revealed that helianthamide adopts a ?-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 ?-defensin fold, which is rarely seen outside of its traditional role in antimicrobial peptides.

SUBMITTER: Tysoe C 

PROVIDER: S-EPMC4819454 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature