Chemoenzymatic Late-Stage Modifications Enable Downstream Click-Mediated Fluorescent Tagging of Peptides

Alessandro Colombano, Luca Dalponte, Sergio Dall'Angelo, Claudia Clemente, Mohannad Salahaldin Idress, Ahmad Ghazal, Wael E Houssen

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Aromatic prenyltransferases from cyanobactin biosynthetic pathways catalyse the chemoselective and regioselective intramolecular transfer of prenyl/geranyl groups from isoprene donors to an electron-rich position in these macrocyclic and linear peptides. These enzymes often demonstrate relaxed substrate specificity and are considered useful biocatalysts for structural diversification of peptides. Here, we assess the isoprene donor specificity of the N1-tryptophan prenyltransferase AcyF from anacyclamide A8P pathway, using a library of 22 synthetic alkyl-pyrophosphate analogues, of which, many display reactive groups that are amenable to additional functionalisation. We further used AcyF to introduce a reactive moiety in a tryptophan-containing cyclic peptide and subsequently used click chemistry to fluorescently label the enzymatically modified peptide. This chemoenzymatic strategy allows late-stage modification of peptides and is highly useful for many applications.
Original languageEnglish
Article numbere202215979
Number of pages7
JournalAngewandte Chemie International Edition
Issue number16
Early online date23 Feb 2023
Publication statusPublished - 11 Apr 2023

Bibliographical note

This project was supported by a fellowship grant from the EPSRC (no. EP/S027246/1, W.E.H.), CC is funded by a PhD studentship from University of Aberdeen. LD was funded by the IBioIC CTP PhD programme. The authors would like to express deep gratitude to Dr Juraj Bella (University of Edinburgh) for his input and technical NMR expertise. The authors are grateful to Dr Ann
Hunter and staff from National Mass Spectrometry Facility at Swansea University for their invaluable support. The authors would like to thank Dr Andrea Holme (University of Aberdeen) and Dr Carlo De Dominicis for their input and valuable discussion.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.


  • Cyclic peptides
  • Cyanobactins
  • Prenyltransferases
  • RiPPs
  • late-stage modification


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