Issue 9, 2017

Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis

Abstract

Halogenation plays a significant role in the activity of the glycopeptide antibiotics (GPAs), although up until now the timing and therefore exact substrate involved was unclear. Here, we present results combined from in vivo and in vitro studies that reveal the substrates for the halogenase enzymes from GPA biosynthesis as amino acid residues bound to peptidyl carrier protein (PCP)-domains from the non-ribosomal peptide synthetase machinery: no activity was detected upon either free amino acids or PCP-bound peptides. Furthermore, we show that the selectivity of GPA halogenase enzymes depends upon both the structure of the bound amino acid and the PCP domain, rather than being driven solely via the PCP domain. These studies provide the first detailed understanding of how halogenation is performed during GPA biosynthesis and highlight the importance and versatility of trans-acting enzymes that operate during peptide assembly by non-ribosomal peptide synthetases.

Graphical abstract: Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis

Supplementary files

Article information

Article type
Edge Article
Submitted
31 Jan 2017
Accepted
20 Jun 2017
First published
13 Jul 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 5992-6004

Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis

T. Kittilä, C. Kittel, J. Tailhades, D. Butz, M. Schoppet, A. Büttner, R. J. A. Goode, R. B. Schittenhelm, K. van Pee, R. D. Süssmuth, W. Wohlleben, M. J. Cryle and E. Stegmann, Chem. Sci., 2017, 8, 5992 DOI: 10.1039/C7SC00460E

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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