Attempting to synthesize lasso peptides using high pressure.

Mateusz Waliczek,Magdalena Wierzbicka,Kacper Szczepski,Piotr Stefanowicz,Łukasz Jaremko,Amanda Sroczyńska,Maciej Arkuszewski,Monika Kijewska,Priyadharshni Rajagopal,Mariusz Jaremko

doi:10.1371/journal.pone.0234901

Mateusz Waliczek, Magdalena Wierzbicka + Show 8 more

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https://doi.org/10.1371/journal.pone.0234901

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Abstract

Lasso peptides are unique in that the tail of the lasso peptide threads through its macrolactam ring. The unusual structure and biological activity of lasso peptides have generated increased interest from the scientific community in recent years. Because of this, many new types of lasso peptides have been discovered. These peptides can be synthesized by microorganisms efficiently, and yet, their chemical assembly is challenging. Herein, we investigated the possibility of high pressure inducing the cyclization of linear precursors of lasso peptides. Unlike other molecules like rotaxanes which mechanically interlock at high pressure, the threaded lasso peptides did not form, even at pressures the high pressure up to 14 000 kbar.

Highlights

Lasso peptides belong to a specific class of natural peptides characterized by a unique “knot” structure motif [1]
We did not expect that assembling these peptides in such manner would enable the formation of the lasso topology, as Lear and Co. [9] reported that the chemical synthesis of lassomycin produced a branched-cyclic peptide
The data reported in literature suggest that, in many cases, the application of high pressure facilitates the formation of mechanically interlocked structures like rotaxanes [25]

Summary

Introduction

Lasso peptides belong to a specific class of natural peptides characterized by a unique “knot” structure motif [1]. The peptide precursor is genetically encoded, but the target structure is formed by a set of several enzymes These peptides are built from a macrolactam ring formed from an isopeptide bond between an N-terminal amino acid residue (usually glycine or alanine) and a side chain of aspartic or glutamic acid. Its structure remains uncertain, and data reported in the literature show conflicting information about whether or not lassomycin has the characteristic “knot” motif [7, 8, and 9]. This does not imply, that the structures of lasso peptides are completely undeterminable. There are many examples of lasso peptides for which the topology has been established with certainty, including

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