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

Tiia Kittilä, Claudia Kittel, Julien Tailhades, Diane Butz, Melanie Schoppet, Anita Büttner, Rob J.A. Goode, Ralf B. Schittenhelm, Karl Heinz Van Pee, Roderich D. Süssmuth, Wolfgang Wohlleben, Max J. Cryle, Evi Stegmann

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)5992-6004
Number of pages13
JournalChemical Science
Volume8
Issue number9
DOIs
Publication statusPublished - 13 Jul 2017

Cite this

Kittilä, Tiia ; Kittel, Claudia ; Tailhades, Julien ; Butz, Diane ; Schoppet, Melanie ; Büttner, Anita ; Goode, Rob J.A. ; Schittenhelm, Ralf B. ; Van Pee, Karl Heinz ; Süssmuth, Roderich D. ; Wohlleben, Wolfgang ; Cryle, Max J. ; Stegmann, Evi. / Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis. In: Chemical Science. 2017 ; Vol. 8, No. 9. pp. 5992-6004.
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title = "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.",
author = "Tiia Kittil{\"a} and Claudia Kittel and Julien Tailhades and Diane Butz and Melanie Schoppet and Anita B{\"u}ttner and Goode, {Rob J.A.} and Schittenhelm, {Ralf B.} and {Van Pee}, {Karl Heinz} and S{\"u}ssmuth, {Roderich D.} and Wolfgang Wohlleben and Cryle, {Max J.} and Evi Stegmann",
year = "2017",
month = "7",
day = "13",
doi = "10.1039/c7sc00460e",
language = "English",
volume = "8",
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Kittilä, T, Kittel, C, Tailhades, J, Butz, D, Schoppet, M, Büttner, A, Goode, RJA, Schittenhelm, RB, Van Pee, KH, Süssmuth, RD, Wohlleben, W, Cryle, MJ & Stegmann, E 2017, 'Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis' Chemical Science, vol. 8, no. 9, pp. 5992-6004. https://doi.org/10.1039/c7sc00460e

Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis. / Kittilä, Tiia; Kittel, Claudia; Tailhades, Julien; Butz, Diane; Schoppet, Melanie; Büttner, Anita; Goode, Rob J.A.; Schittenhelm, Ralf B.; Van Pee, Karl Heinz; Süssmuth, Roderich D.; Wohlleben, Wolfgang; Cryle, Max J.; Stegmann, Evi.

In: Chemical Science, Vol. 8, No. 9, 13.07.2017, p. 5992-6004.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis

AU - Kittilä, Tiia

AU - Kittel, Claudia

AU - Tailhades, Julien

AU - Butz, Diane

AU - Schoppet, Melanie

AU - Büttner, Anita

AU - Goode, Rob J.A.

AU - Schittenhelm, Ralf B.

AU - Van Pee, Karl Heinz

AU - Süssmuth, Roderich D.

AU - Wohlleben, Wolfgang

AU - Cryle, Max J.

AU - Stegmann, Evi

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