Planta Med 2013; 79 - CL2
DOI: 10.1055/s-0033-1348527

Discovery of a Novel Class II Lasso Peptide from Streptomyces sp. RKKD-790

K Gill 1, F Berrue 1, J Pearson 1, R Kerr 1, 2
  • 1Department of Chemistry, University of Prince Edward Island, Charlottetown, PE, C1A 4P3
  • 2Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown PE, C1A 4P3

Streptomyces sp. RKKD-790 produces a novel class II lasso peptide consisting of 15 amino acids. The lasso fold is formed by the C-terminal tail irreversibly threading through a macrolactam ring formed between glycine at the N-terminus and aspartic acid at the eighth amino acid position. The threaded structure is held in place by Trp-14 and Leu-15 which act as bulky steric locks that prevent the linear tail from unthreading. Lasso peptides are extremely stable due to this threaded structure and make effective molecular scaffolds for drug design. This is the smallest lasso peptide isolated to date and provides an example of the minimum structural features required to form the knotted structure. It was discovered by analyzing LCMS profiles of a library of bacterial fermentation extracts using the multivariate statistic tool Principal Component Analysis. The structure was elucidated using NMR spectroscopy and the lasso fold was determined using tandem mass spectrometry and computational modeling from NOE distance constraints. The discovery, isolation and structure elucidation of this novel peptide will be presented.