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Reply to "Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases"

Nature Chemical Biology volume 9, page 137 (2013)Cite this article

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Greiner et al . reply—in our paper1, we presented several lines of evidence that chaetocin functions as specific inhibitor of SU(VAR)3-9. We had initially concluded that the disulfide warhead was not essential for chaetocin's inhibitory capacity on the basis of our observation of substantial inhibition of Drosophila melanogaster SU(VAR)3-9 by chaetocin, even in the presence of high concentrations of DTT1. Cherblanc et al.2 now revisit this issue in the context of SUV39H1, the human ortholog of SU(VAR)3-9.

We note that Cherblanc et al.2 find a IC50 for hSUV39H1 similar to that observed in our initial experiments. However, the availability of new compounds has enabled them to directly test our initial hypothesis. Their use of 2, lacking chaetocin's disulfides, indeed suggests that, in contrast to our initial hypothesis, the disulfide bond within chaetocin has a substantial role. However, it is interesting that a structurally divergent ETP model compound (3) containing the disulfide bond has a 30-fold higher IC50. This clearly suggests that chaetocin does not solely inhibit Drosophila SU(VAR)3-9 activity through the presence of its disulfide bonds (which 3 has as well) but also direct binding to the enzyme.

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References

  1. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. Nat. Chem. Biol. 1, 143–145 (2006).

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  2. Cherblanc, F.L., Chapman, K.L., Brown, R. & Fuchter, M.J. Nat. Chem. Biol. 9, 136–137 (2013).

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Acknowledgements

The work has been supported by a predoctoral grant to D.G. from the School of Medicine from the Ludwig-Maximillians University of Munich (MolMed).

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  1. Ernst Roemer

    Present address: Present address: Institut für Pflanzenbiochemie, Universität Halle, Halle (Saale), Germany.,

Authors and Affiliations

  1. Department of Molecular Biology, Adolf Butenandt Institute, Histone Modifications Group, Ludwig-Maximillians University of Munich, Munich, Germany

    Dorothea Greiner, Tiziana Bonaldi, Ragnhild Eskeland & Axel Imhof

  2. Abteilung Molekulare Naturstoff-Forschung, Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie–Hans-Knöll-Institut für Naturstoff-Forschung, Jena, Germany

    Ernst Roemer

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  1. Dorothea Greiner
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  2. Tiziana Bonaldi
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  3. Ragnhild Eskeland
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  4. Ernst Roemer
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  5. Axel Imhof
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Correspondence to Axel Imhof.

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Greiner, D., Bonaldi, T., Eskeland, R. et al. Reply to "Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases". Nat Chem Biol 9, 137 (2013). https://doi.org/10.1038/nchembio.1188

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