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Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways

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Abstract

Lanthipeptides are characterized by thioether crosslinks formed by post-translational modifications. The cyclization process that favors a single ring pattern over many other possible ring patterns has been the topic of much speculation. Recent studies suggest that for some systems the cyclization pattern and stereochemistry is determined not by the enzyme, but by the sequence of the precursor peptide. However, the factors that govern the outcome of the cyclization process are not understood. This study presents the three-dimensional structures of seven lanthipeptides determined by nuclear magnetic resonance spectroscopy, including five prochlorosins and the two peptides that make up cytolysin, a virulence factor produced by Enterococcus faecalis that is directly linked to human disease. These peptides were chosen because their substrate sequence determines either the ring pattern (prochlorosins) or the stereochemistry of cyclization (cytolysins). We present the structures of prochlorosins 1.1, 2.1, 2.8, 2.10 and 2.11, the first three-dimensional structures of prochlorosins. Our findings provide insights into the molecular determinants of cyclization as well as why some prochlorosins may be better starting points for library generation than others. The structures of the large and small subunits of the enterococcal cytolysin show that these peptides have long helical stretches, a rare observation for lanthipeptides characterized to date. These helices may explain their pore forming activity and suggest that the small subunit may recognize a molecular target followed by recruitment of the large subunit to span the membrane.

Graphical abstract: Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways

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Supplementary files

Article information


Submitted
20 Mar 2020
Accepted
23 Jun 2020
First published
25 Jun 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways

S. C. Bobeica, L. Zhu, J. Z. Acedo, W. Tang and W. A. van der Donk, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC01651A

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