CHAPTER 10: An Introduction to Bacterial Lasso Peptides

Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs), whose defining structural feature is a macrocycle at the N-terminus that is threaded by the linear C-terminal peptide tail. Such peptides with [1]rotaxane topology have so far been inaccessible by chemical synthesis and are widely found in bacteria. In this book chapter, we give an overview of what is known about the different classes of these compounds, and their biosynthetic machinery and biological functions. We discuss known biosynthetic gene cluster arrangements and review methods for genome mining of these compounds. In addition, methods for structural elucidation of their unique fold will be summarized and techniques are described to prove their topology when NMR or X-ray structure elucidation is not an option (e.g. mutational analysis, protease assays, thermal stability tests, IM-MS). Finally, an overview of all identified biological activities of known lasso peptides is given and their potential for use in drug development will be explored. Taken together, this book chapter gives a concise summary of the current state of the research field and explains the basic toolbox for working with and characterizing these interesting natural compounds.