Investigations on the mode of action of gephyronic acid, an inhibitor of eukaryotic protein translation from myxobacteria
- The identification of inhibitors of eukaryotic protein biosynthesis, which are targeting single translation factors, is highly demanded. Here we report on a small molecule inhibitor, gephyronic acid, isolated from the myxobacterium Archangium gephyra that inhibits growth of transformed mammalian cell lines in the nM range. In direct comparison, primary human fibroblasts were shown to be less sensitive to toxic effects of gephyronic acid than cancer-derived cells. Gephyronic acid is targeting the protein translation system. Experiments with IRES dual luciferase reporter assays identified it as an inhibitor of the translation initiation. DARTs approaches, co-localization studies and pull-down assays indicate that the binding partner could be the eukaryotic initiation factor 2 subunit alpha (eIF2α). Gephyronic acid seems to have a different mode of action than the structurally related polyketides tedanolide, myriaporone, and pederin and is a valuable tool for investigating the eukaryotic translation system. Because cancer derived cells were found to be especially sensitive, gephyronic acid could potentially find use as a drug candidate.
Author: | Yazh Muthukumar, Johanna Münkemer, Daniel Mathieu, Christian RichterORCiDGND, Harald SchwalbeORCiDGND, Heinrich Steinmetz, Wolfgang Kessler, Joachim Reichelt, Ulrike Beutling, Ronald Frank, Konrad Büssow, Joop van den Heuvel, Mark Brönstrup, Richard E. Taylor, Sabine Laschat, Florenz Sasse |
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URN: | urn:nbn:de:hebis:30:3-468867 |
DOI: | https://doi.org/10.1371/journal.pone.0201605 |
ISSN: | 1932-6203 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/30063768 |
Parent Title (English): | PLoS one |
Publisher: | PLoS |
Place of publication: | Lawrence, Kan. |
Contributor(s): | Arun Rishi |
Document Type: | Article |
Language: | English |
Year of Completion: | 2018 |
Date of first Publication: | 2018/07/31 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2018/08/02 |
Tag: | Biotin; Esters; Eukaryota; Internal ribosome entry site; Luciferase; Phosphorylation; Protein translation; Translation initiation |
Volume: | 13 |
Issue: | (7): e0201605 |
Page Number: | 14 |
First Page: | 1 |
Last Page: | 14 |
Note: | This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. |
HeBIS-PPN: | 435671634 |
Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe | |
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs | |
Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ) | |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Sammlungen: | Universitätspublikationen |
Licence (German): | Gemeinfreies Werk / Public Domain |