Sactipeptide Engineering by Probing the Substrate Tolerance of a Thioether-Bond-Forming Sactisynthase.

Bioengineering Miniproteins RiPPs Sactipeptides Sactisynthases

Journal

Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543

Informations de publication

Date de publication:
07 11 2022
Historique:
received: 24 07 2022
pubmed: 2 9 2022
medline: 3 11 2022
entrez: 1 9 2022
Statut: ppublish

Résumé

Sactipeptides are ribosomally synthesized peptides containing a unique sulfur to α-carbon crosslink. Catalyzed by sactisynthases, this thioether pattern endows sactipeptides with enhanced structural, thermal, and proteolytic stability, which makes them attractive scaffolds for the development of novel biotherapeutics. Herein, we report the in-depth study on the substrate tolerance of the sactisynthase AlbA to catalyze the formation of thioether bridges in sactipeptides. We identified a possible modification site within the sactipeptide subtilosin A allowing for peptide engineering without compromising formation of thioether bridges. A panel of natural and hybrid sactipeptides was produced to study the AlbA-mediated formation of thioether bridges, which were identified mass-spectrometrically. In a proof-of-principle study, we re-engineered subtilosin A to a thioether-bridged, specific streptavidin targeting peptide, opening the door for the functional engineering of sactipeptides.

Identifiants

pubmed: 36049110
doi: 10.1002/anie.202210883
pmc: PMC9828075
doi:

Substances chimiques

Sulfides 0
Peptides 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e202210883

Informations de copyright

© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

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Auteurs

Ataurehman Ali (A)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Dominic Happel (D)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Jan Habermann (J)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Katrin Schoenfeld (K)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Arturo Macarrón Palacios (A)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Sebastian Bitsch (S)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Simon Englert (S)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Hendrik Schneider (H)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Olga Avrutina (O)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.

Sebastian Fabritz (S)

Department of Chemical Biology, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.

Harald Kolmar (H)

Department for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, 64287, Darmstadt, Germany.
Centre for Synthetic Biology, Technical University of Darmstadt, 64283, Damstadt, Germany.

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Classifications MeSH