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Role of pnc A gene mutations W68R and W68G in pyrazinamide resistance
Author(s) -
Aggarwal Mansi,
Singh Aditi,
Grover Sonam,
Pandey Bharati,
Kumari Anchala,
Grover Abhinav
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26420
Subject(s) - mutant , mycobacterium tuberculosis , pyrazinamide , docking (animal) , gene , biology , drug resistance , binding site , plasma protein binding , genetics , biochemistry , microbiology and biotechnology , tuberculosis , medicine , nursing , pathology
Mycobacterium tuberculosis (Mtb) resistance toward anti‐tuberculosis drugs is a widespread problem. Pyrazinamide (PZA) is a first line antitubercular drug that kills semi‐dormant bacilli when converted into its activated form, that is, pyrazinoic acid (POA) by Pyrazinamidase (PZase) enzyme coded by pnc A gene. In this study, we conducted several analyses on native and mutant structures (W68R, W68G) of PZase before and after docking with the PZA drug to explore the molecular mechanism behind PZA resistance caused due to pnc A mutations. Structural changes caused by mutations were studied with respect to their effects on functionality of protein. Docking was performed to analyze the protein‐drug binding and comparative analysis was done to observe how the mutations affect drug binding affinity and binding site on protein. Native PZase protein was observed to have the maximum binding affinity in terms of docking score as well as shape complementarity in comparison to the mutant forms. Molecular dynamics simulation analyses showed that mutation in the 68th residue of protein results in a structural change at its active site which further affects the biological function of protein, that is, conversion of PZA to POA. Mutations in the protein thereby led to PZA resistance in the bacterium due to the inefficient binding.