期刊
FEBS JOURNAL
卷 281, 期 19, 页码 4351-4366出版社
WILEY
DOI: 10.1111/febs.12939
关键词
cis-proline; cystine knot; pseudocyclics; wrightide; alpha-amylase inhibitors
资金
- National Research Foundation in Singapore [NRF-CRP8-2011-05]
Obesity and type 2 diabetes are chronic metabolic diseases, and those affected could benefit from the use of alpha-amylase inhibitors to manage starch intake. The pseudocyclics, wrightides Wr-AI1 to Wr-AI3, isolated from an Apocynaceae plant show promise for further development as orally active alpha-amylase inhibitors. These linear peptides retain the stability known for cystine-knot peptides in the presence of harsh treatment. They are resistant to heat treatment and endopeptidase and exopeptidase degradation, which is characteristic of cyclic cystine-knot peptides. Our NMR and crystallography analysis also showed that wrightides, which are currently the smallest proteinaceous alpha-amylase inhibitors reported, contain the backbone-twisting cis-proline, which is preceded by a nonaromatic residue rather than a conventional aromatic residue. The modeled structure and a molecular dynamics study of Wr-AI1 in complex with yellow mealworm alpha-amylase suggested that, despite having a similar structure and cystine-knot fold, the knottin-type alpha-amylase inhibitors may bind to insect alpha-amylase via a different set of interactions. Finally, we showed that the precursors of pseudocyclic cystine-knot alpha-amylase inhibitors and their biosynthesis in plants follow a secretory protein synthesis pathway. Together, our findings provide insights for the use of the pseudocyclic alpha-amylase inhibitors as useful leads for the development of orally active peptidyl bioactives, as well as an alternative scaffold for cyclic peptides for engineering metabolically stable human alpha-amylase inhibitors.
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