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Investigations on the mode of action of gephyronic acid, an inhibitor of eukaryotic protein translation from myxobacteria.
Muthukumar, Yazh Münkemer, Johanna Mathieu, Daniel Richter, Christian Schwalbe, Harald Steinmetz, Heinrich Kessler, Wolfgang Reichelt, Joachim Beutling, Ulrike Frank, Ronald
Muthukumar, Yazh
Münkemer, Johanna
Mathieu, Daniel
Richter, Christian
Schwalbe, Harald
Steinmetz, Heinrich
Kessler, Wolfgang
Reichelt, Joachim
Beutling, Ulrike
Frank, Ronald
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2018-01-01
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Abstract
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.
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PLoS One. 2018 Jul 31;13(7):e0201605. doi: 10.1371/journal.pone.0201605 eCollection 2018.
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1932-6203
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Attribution-NonCommercial-ShareAlike 4.0 International