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Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism
Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols,...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9814637/ https://www.ncbi.nlm.nih.gov/pubmed/36697631 http://dx.doi.org/10.1038/s42004-021-00600-4 |
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author | Terenzi, Alessio La Franca, Mery van Schoonhoven, Sushilla Panchuk, Rostyslav Martínez, Álvaro Heffeter, Petra Gober, Redding Pirker, Christine Vician, Petra Kowol, Christian R. Stoika, Rostyslav Salassa, Luca Rohr, Jürgen Berger, Walter |
author_facet | Terenzi, Alessio La Franca, Mery van Schoonhoven, Sushilla Panchuk, Rostyslav Martínez, Álvaro Heffeter, Petra Gober, Redding Pirker, Christine Vician, Petra Kowol, Christian R. Stoika, Rostyslav Salassa, Luca Rohr, Jürgen Berger, Walter |
author_sort | Terenzi, Alessio |
collection | PubMed |
description | Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism. |
format | Online Article Text |
id | pubmed-9814637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98146372023-01-10 Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism Terenzi, Alessio La Franca, Mery van Schoonhoven, Sushilla Panchuk, Rostyslav Martínez, Álvaro Heffeter, Petra Gober, Redding Pirker, Christine Vician, Petra Kowol, Christian R. Stoika, Rostyslav Salassa, Luca Rohr, Jürgen Berger, Walter Commun Chem Article Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism. Nature Publishing Group UK 2021-11-25 /pmc/articles/PMC9814637/ /pubmed/36697631 http://dx.doi.org/10.1038/s42004-021-00600-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Terenzi, Alessio La Franca, Mery van Schoonhoven, Sushilla Panchuk, Rostyslav Martínez, Álvaro Heffeter, Petra Gober, Redding Pirker, Christine Vician, Petra Kowol, Christian R. Stoika, Rostyslav Salassa, Luca Rohr, Jürgen Berger, Walter Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism |
title | Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism |
title_full | Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism |
title_fullStr | Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism |
title_full_unstemmed | Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism |
title_short | Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism |
title_sort | landomycins as glutathione-depleting agents and natural fluorescent probes for cellular michael adduct-dependent quinone metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9814637/ https://www.ncbi.nlm.nih.gov/pubmed/36697631 http://dx.doi.org/10.1038/s42004-021-00600-4 |
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