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|Title:||Pyrazinamide triggers degradation of its target aspartate decarboxylase||Authors:||Gopal, Pooja
Sarathy, Jickky Palmae
Lim, Teck Kwang
Rubin, Eric J.
Science::Biological sciences::Molecular biology
|Issue Date:||2020||Source:||Gopal, P., Sarathy, J. P., Yee, M., Ragunathan, P., Shin, J., Bhushan, S., . . . Dick, T. (2020). Pyrazinamide triggers degradation of its target aspartate decarboxylase. Nature Communications, 11, 1661-. doi:10.1038/s41467-020-15516-1||Journal:||Nature Communications||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.||URI:||https://hdl.handle.net/10356/138824||ISSN:||2041-1723||DOI:||10.1038/s41467-020-15516-1||Rights:||© 2020 The Author(s). 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/.||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Journal Articles|
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