- Title
- Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics
- Creator
- Barozi, Victor
- Creator
- Musyoka, Thommas M
- Creator
- Sheik Amamuddy, Olivier
- Creator
- Tastan Bishop, Özlem
- Subject
- To be catalogued
- Date Issued
- 2022
- Date
- 2022
- Type
- text
- Type
- article
- Identifier
- http://hdl.handle.net/10962/474493
- Identifier
- vital:77713
- Identifier
- https://doi.org/10.1021/acsomega.2c01036
- Description
- Resistance mutations in Mycobacterium tuberculosis (Mtb) catalase peroxidase protein (KatG), an essential enzyme in isoniazid (INH) activation, reduce the sensitivity of Mtb to first-line drugs, hence presenting challenges in tuberculosis (TB) management. Thus, understanding the mutational imposed resistance mechanisms remains of utmost importance in the quest to reduce the TB burden. Herein, effects of 11 high confidence mutations in the KatG structure and residue network communication patterns were determined using extensive computational approaches. Combined traditional post-molecular dynamics analysis and comparative essential dynamics revealed that the mutant proteins have significant loop flexibility around the heme binding pocket and enhanced asymmetric protomer behavior with respect to wild-type (WT) protein. Heme contact analysis between WT and mutant proteins identified a reduction to no contact between heme and residue His270, a covalent bond vital for the heme-enabled KatG catalytic activity. Betweenness centrality calculations showed large hub ensembles with new hubs especially around the binding cavity and expanded to the dimerization domain via interface in the mutant systems, providing possible compensatory allosteric communication paths for the active site as a result of the mutations which may destabilize the heme binding pocket and the loops in its vicinity. Additionally, an interesting observation came from Eigencentrality hubs, most of which are located in the C-terminal domain, indicating relevance of the domain in the protease functionality. Overall, our results provide insight toward the mechanisms involved in KatG-INH resistance in addition to identifying key regions in the enzyme functionality, which can be used for future drug design.
- Format
- 20 pages
- Format
- Language
- English
- Relation
- ACS Omega
- Relation
- Barozi, V., Musyoka, T. M., Sheik Amamuddy, O., and Tastan Bishop, O. (2022). Deciphering isoniazid drug resistance mechanisms on dimeric Mycobacterium tuberculosis KatG via post-molecular dynamics analyses including combined dynamic residue network metrics. ACS omega, 7(15), 13313-13332. https://doi.org/10.1021/acsomega.2c01036
- Relation
- ACS Omega volume 7 number 15 13313 13332 2022 2470-1343
- Rights
- Author
- Rights
- Use of this resource is governed by the terms and conditions of the Creative Commons CC BY-NC-ND 4.0 License (Attribution-NonCommercial-NoDerivatives 4.0 International) https://creativecommons.org/licenses/by-nc-nd/4.0/
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Sheik Amamuddy, Olivier (Dr)
Tastan Bishop, Ozlem (Prof)
SDG 03. Good Health and Well-Being
RU Department of Biochemistry, Microbiology and Bioinformatics
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