Natural and Engineered Strategies for Peptide Cyclization

Florian Kopp and Mohamed A. Marahiel

Faculty of Chemistry, University of Marburg, Hans-Meerwein-Straße, 35032 Marburg, Germany




Macrocyclization is a key structural feature of many diverse natural products, including polyketides, nonribosomal peptides and other biologically active peptides and proteins. In nonribosomally synthezised peptides, macrocyclization is commonly achieved via the formation of intramolecular esters (macrolactone) or amides (macrolactam).

During biosynthesis, this crucial step is accomplished by so called thioesterase domains (cyclases) that have been capable of peptide cyclization of artificial substrate analogues in vitro. Due to cleavage of the reaction intermediate by water rather than the desired intramolecular nucleophile, hydrolysis leads to severe product loss in many cyclization procedures. Therefore, the chemoenzymatic strategy has been transferred from aqueous solution to organic solvents and lead to quantitative cyclic product formation. Further a rational enzym design approach allowed the in vitro engineering of the the surfactin cyclase (Srf TE) to catalyse macrolactam instead of macrolactone formation. Additionally, we recently studied the formation of a unique kind of macrocyclic imines called nostocyclopeptides. Based on in vitro studies with a recombinant reductase domain (R-domain), chemically derived peptidyl-substrates and peptide aldehydes, we established a model for the self-assembly of the macrocyclic imine.