Pyrazinamide resistance and mutations L19R, R140H, and E144K in Pyrazinamidase of Mycobacterium tuberculosis.
mutations
pncA
pyrazinamidase (PZase)
pyrazinamide (PZA)
simulations
Journal
Journal of cellular biochemistry
ISSN: 1097-4644
Titre abrégé: J Cell Biochem
Pays: United States
ID NLM: 8205768
Informations de publication
Date de publication:
May 2019
May 2019
Historique:
received:
24
07
2018
accepted:
08
10
2018
pubmed:
30
11
2018
medline:
30
11
2018
entrez:
29
11
2018
Statut:
ppublish
Résumé
Pyrazinamide (PZA) is an important component of first-line antituberculosis drugs activated by Mycobacterium tuberculosis pyrazinamidase (PZase) into its active form pyrazinoic acid. Mutations in the pncA gene have been recognized as the major cause of PZA resistance. We detected some novel mutations, Leucine19Arginine (L19R), Arginine140Histidine (R140H), and Glutamic acid144 Lysine (E144K), in the pncA gene of PZA-resistant isolates in our wet lab PZA drug susceptibility testing and sequencing. As the molecular mechanism of resistance of these variants has not been reported earlier, we have performed multiple analyses to unveil different mechanisms of resistance because of PZase mutations L19R, R140H, and E144K. The mutants and native PZase structures were subjected to comprehensive computational molecular dynamics (MD) simulations at 100 nanoseconds in apo and drug-bound form. Mutants and native PZase binding pocket were compared to observe the consequence of mutations on the binding pocket size. Hydrogen bonding, Gibbs free energy, and natural ligand Fe
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7154-7166Subventions
Organisme : Higher Education Commission, Pakistan
ID : IRSIP No: 1-8/HEC/HRD/2017/8392
Organisme : Ministry of Science and Technology of China, National Natural Science Foundation of China and Center for High Performance Computing, Shanghai Jiao Tong University
ID : 61832019
Organisme : Ministry of Science and Technology of China, National Natural Science Foundation of China and Center for High Performance Computing, Shanghai Jiao Tong University
ID : 2016YFA0501703
Organisme : Ministry of Science and Technology of China, National Natural Science Foundation of China and Center for High Performance Computing, Shanghai Jiao Tong University
ID : YG2017ZD14
Organisme : Ministry of Science and Technology of China, National Natural Science Foundation of China and Center for High Performance Computing, Shanghai Jiao Tong University
ID : 61503244
Organisme : State Key Lab on Microbial Metabolism
Organisme : Joint Research Funds for Medical and Engineering & Scientific Research at Shanghai Jiao Tong University
ID : YG2017ZD14
Organisme : Center for High Performance Computing, Shanghai Jiao Tong University
Informations de copyright
© 2018 Wiley Periodicals, Inc.