Issue 9, 2023

Biosynthetic incorporation of fluorinated amino acids into the nonribosomal peptide gramicidin S

Abstract

Fluorine is a key element in medicinal chemistry, as it can significantly enhance the pharmacological properties of drugs. In this study, we aimed to biosynthetically produce fluorinated analogues of the antimicrobial cyclic decapeptide gramicidin S (GS). However, our results show that the A-domain of the NRPS module GrsA rejects 4-fluorinated analogues of its native substrate Phe due to an interrupted T-shaped aromatic interaction in the binding pocket. We demonstrate that GrsA mutant W239S improves the incorporation of 4-fluorinated Phe into GS both in vitro and in vivo. Our findings provide new insights into the behavior of NRPSs towards fluorinated amino acids and strategies for the engineered biosynthesis of fluorinated peptides.

Graphical abstract: Biosynthetic incorporation of fluorinated amino acids into the nonribosomal peptide gramicidin S

Supplementary files

Article information

Article type
Paper
Submitted
30 Apr. 2023
Accepted
24 Jūl. 2023
First published
25 Jūl. 2023
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2023,4, 692-697

Biosynthetic incorporation of fluorinated amino acids into the nonribosomal peptide gramicidin S

M. Müll, F. Pourmasoumi, L. Wehrhan, O. Nosovska, P. Stephan, H. Zeihe, I. Vilotijevic, B. G. Keller and H. Kries, RSC Chem. Biol., 2023, 4, 692 DOI: 10.1039/D3CB00061C

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