Issue 8, 2016

A widespread bacterial phenazine forms S-conjugates with biogenic thiols and crosslinks proteins

Abstract

Phenazines are redox-active compounds produced by a range of bacteria, including many pathogens. Endowed with various biological activities, these ubiquitous N-heterocycles are well known for their ability to generate reactive oxygen species by redox cycling. Phenazines may lead to an irreversible depletion of glutathione, but a detailed mechanism has remained elusive. Furthermore, it is not understood why phenazines have so many protein targets and cause protein misfolding as well as their aggregation. Here we report the discovery of unprecedented conjugates (panphenazines A, B) of panthetheine and phenazine-1-carboxylic (PCA) acid from a Kitasatospora sp., which prompted us to investigate their biogenesis. We found that PCA reacts with diverse biogenic thiols under radical-forming conditions, which provides a plausible model for irreversible glutathione depletion. To evaluate the scope of the reaction in cells we designed biotin and rhodamine conjugates for protein labelling and examined their covalent fusion with model proteins (ketosynthase, carbonic anhydrase III, albumin). Our results reveal important, yet overlooked biological roles of phenazines and show for the first time their function in protein conjugation and crosslinking.

Graphical abstract: A widespread bacterial phenazine forms S-conjugates with biogenic thiols and crosslinks proteins

Supplementary files

Article information

Article type
Edge Article
Submitted
01 Feb 2016
Accepted
13 Apr 2016
First published
14 Apr 2016
This article is Open Access

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

Chem. Sci., 2016,7, 4848-4855

A widespread bacterial phenazine forms S-conjugates with biogenic thiols and crosslinks proteins

D. Heine, S. Sundaram, M. Beudert, K. Martin and C. Hertweck, Chem. Sci., 2016, 7, 4848 DOI: 10.1039/C6SC00503A

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements