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https://doi.org/10.1038/s41467-020-15516-1
Title: | Pyrazinamide triggers degradation of its target aspartate decarboxylase | Authors: | Gopal, P. Sarathy, J.P. Yee, M. Ragunathan, P. Shin, J. Bhushan, S. Zhu, J. Akopian, T. Kandror, O. Lim, T.K. Gengenbacher, M. Lin, Q. Rubin, E.J. Grüber, G. Dick, T. |
Issue Date: | 2020 | Publisher: | Nature Research | Citation: | Gopal, P., Sarathy, J.P., Yee, M., Ragunathan, P., Shin, J., Bhushan, S., Zhu, J., Akopian, T., Kandror, O., Lim, T.K., Gengenbacher, M., Lin, Q., Rubin, E.J., Grüber, G., Dick, T. (2020). Pyrazinamide triggers degradation of its target aspartate decarboxylase. Nature Communications 11 (1) : 1661. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-020-15516-1 | Rights: | Attribution 4.0 International | Abstract: | Pyrazinamide is a sterilizing first-line tuberculosis drug. Genetic, metabolomic and biophysical analyses previously demonstrated that pyrazinoic acid, the bioactive form of the prodrug pyrazinamide (PZA), interrupts biosynthesis of coenzyme A in Mycobacterium tuberculosis by binding to aspartate decarboxylase PanD. While most drugs act by inhibiting protein function upon target binding, we find here that pyrazinoic acid is only a weak enzyme inhibitor. We show that binding of pyrazinoic acid to PanD triggers degradation of the protein by the caseinolytic protease ClpC1-ClpP. Thus, the old tuberculosis drug pyrazinamide exerts antibacterial activity by acting as a target degrader, a mechanism of action that has recently emerged as a successful strategy in drug discovery across disease indications. Our findings provide the basis for the rational discovery of next generation PZA. © 2020, The Author(s). | Source Title: | Nature Communications | URI: | https://scholarbank.nus.edu.sg/handle/10635/199047 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-020-15516-1 | Rights: | Attribution 4.0 International |
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