Please use this identifier to cite or link to this item:
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.
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
ISSN: 2041-1723
DOI: 10.1038/s41467-020-15516-1
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1038_s41467_020_15516_1.pdf1.55 MBAdobe PDF



Google ScholarTM



This item is licensed under a Creative Commons License Creative Commons