Pyrazinamide triggers degradation of its target aspartate decarboxylase
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 de...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2020
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| Online Access: | https://hdl.handle.net/10356/138824 |
| _version_ | 1826129503350423552 |
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| author | Gopal, Pooja Sarathy, Jickky Palmae Yee, Michelle Ragunathan, Priya Shin, Joon Bhushan, Shashi Zhu, Junhao Akopian, Tatos Kandror, Olga Lim, Teck Kwang Gengenbacher, Martin Lin, Qingsong Rubin, Eric J. Grüber, Gerhard Dick, Thomas |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Gopal, Pooja Sarathy, Jickky Palmae Yee, Michelle Ragunathan, Priya Shin, Joon Bhushan, Shashi Zhu, Junhao Akopian, Tatos Kandror, Olga Lim, Teck Kwang Gengenbacher, Martin Lin, Qingsong Rubin, Eric J. Grüber, Gerhard Dick, Thomas |
| author_sort | Gopal, Pooja |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T07:41:40Z |
| format | Journal Article |
| id | ntu-10356/138824 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:41:40Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1388242023-02-28T17:09:46Z Pyrazinamide triggers degradation of its target aspartate decarboxylase Gopal, Pooja Sarathy, Jickky Palmae Yee, Michelle Ragunathan, Priya Shin, Joon Bhushan, Shashi Zhu, Junhao Akopian, Tatos Kandror, Olga Lim, Teck Kwang Gengenbacher, Martin Lin, Qingsong Rubin, Eric J. Grüber, Gerhard Dick, Thomas School of Biological Sciences Science::Biological sciences::Biochemistry Science::Biological sciences::Molecular biology Target Identification Tuberculosis 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. NRF (Natl Research Foundation, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version 2020-05-13T04:02:32Z 2020-05-13T04:02:32Z 2020 Journal Article 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 2041-1723 https://hdl.handle.net/10356/138824 10.1038/s41467-020-15516-1 32245967 2-s2.0-85083042668 1 11 en Nature Communications © 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/. application/pdf |
| spellingShingle | Science::Biological sciences::Biochemistry Science::Biological sciences::Molecular biology Target Identification Tuberculosis Gopal, Pooja Sarathy, Jickky Palmae Yee, Michelle Ragunathan, Priya Shin, Joon Bhushan, Shashi Zhu, Junhao Akopian, Tatos Kandror, Olga Lim, Teck Kwang Gengenbacher, Martin Lin, Qingsong Rubin, Eric J. Grüber, Gerhard Dick, Thomas Pyrazinamide triggers degradation of its target aspartate decarboxylase |
| title | Pyrazinamide triggers degradation of its target aspartate decarboxylase |
| title_full | Pyrazinamide triggers degradation of its target aspartate decarboxylase |
| title_fullStr | Pyrazinamide triggers degradation of its target aspartate decarboxylase |
| title_full_unstemmed | Pyrazinamide triggers degradation of its target aspartate decarboxylase |
| title_short | Pyrazinamide triggers degradation of its target aspartate decarboxylase |
| title_sort | pyrazinamide triggers degradation of its target aspartate decarboxylase |
| topic | Science::Biological sciences::Biochemistry Science::Biological sciences::Molecular biology Target Identification Tuberculosis |
| url | https://hdl.handle.net/10356/138824 |
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