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Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis

Isoniazid (INH) is a drug for the treatment of tuberculosis in patients infected with Mycobacterium tuberculosis. The katG enzyme, or catalase-peroxidase, activates the pro-drug INH that is coded by the katG gene in M. tuberculosis. Mutations of the katG gene in M. tuberculosis are a major INH resis...

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Autores principales: Purkan, P, Ihsanawati, I, Natalia, D, Syah, YM, Retnoningrum, DS, Siswanto, I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Carol Davila University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101688/
https://www.ncbi.nlm.nih.gov/pubmed/30140323
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author Purkan, P
Ihsanawati, I
Natalia, D
Syah, YM
Retnoningrum, DS
Siswanto, I
author_facet Purkan, P
Ihsanawati, I
Natalia, D
Syah, YM
Retnoningrum, DS
Siswanto, I
author_sort Purkan, P
collection PubMed
description Isoniazid (INH) is a drug for the treatment of tuberculosis in patients infected with Mycobacterium tuberculosis. The katG enzyme, or catalase-peroxidase, activates the pro-drug INH that is coded by the katG gene in M. tuberculosis. Mutations of the katG gene in M. tuberculosis are a major INH resistance mechanism. The M. tuberculosis clinical isolate R2 showed INH resistance at a high level of 10 µg/mL. However, the molecular basis for the resistance is unclear. The identification of a mutation in the katG gene of the clinical isolate R2 showed four mutations, i.e., C1061T, G1261 A, G1388T, G2161A, which correspond to the amino acid substitutions T354I, G421S, R463L, and V721M, respectively. The mutant katG gene, along with the wild-type were cloned, expressed and purified. The mutant enzyme showed 86.5% of catalase and 45% of peroxidase activities in comparison to the wild type. The substitutions of T(354)I and G(421)S in mutant katG R2 created significant instability in the adduct triad complex (Trp107-Tyr229-Met255), a part of the active site of the catalase-peroxidase enzyme in the model structure analysis. The events could be based on the high resistance of the clinical isolate R2 toward INH as the molecular basis.
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spelling pubmed-61016882018-08-23 Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis Purkan, P Ihsanawati, I Natalia, D Syah, YM Retnoningrum, DS Siswanto, I J Med Life Original Article Isoniazid (INH) is a drug for the treatment of tuberculosis in patients infected with Mycobacterium tuberculosis. The katG enzyme, or catalase-peroxidase, activates the pro-drug INH that is coded by the katG gene in M. tuberculosis. Mutations of the katG gene in M. tuberculosis are a major INH resistance mechanism. The M. tuberculosis clinical isolate R2 showed INH resistance at a high level of 10 µg/mL. However, the molecular basis for the resistance is unclear. The identification of a mutation in the katG gene of the clinical isolate R2 showed four mutations, i.e., C1061T, G1261 A, G1388T, G2161A, which correspond to the amino acid substitutions T354I, G421S, R463L, and V721M, respectively. The mutant katG gene, along with the wild-type were cloned, expressed and purified. The mutant enzyme showed 86.5% of catalase and 45% of peroxidase activities in comparison to the wild type. The substitutions of T(354)I and G(421)S in mutant katG R2 created significant instability in the adduct triad complex (Trp107-Tyr229-Met255), a part of the active site of the catalase-peroxidase enzyme in the model structure analysis. The events could be based on the high resistance of the clinical isolate R2 toward INH as the molecular basis. Carol Davila University Press 2018 /pmc/articles/PMC6101688/ /pubmed/30140323 Text en ©Carol Davila University Press This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Original Article
Purkan, P
Ihsanawati, I
Natalia, D
Syah, YM
Retnoningrum, DS
Siswanto, I
Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis
title Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis
title_full Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis
title_fullStr Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis
title_full_unstemmed Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis
title_short Molecular Analysis of katG Encoding Catalase-Peroxidase from Clinical Isolate of Isoniazid-Resistant Mycobacterium tuberculosis
title_sort molecular analysis of katg encoding catalase-peroxidase from clinical isolate of isoniazid-resistant mycobacterium tuberculosis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101688/
https://www.ncbi.nlm.nih.gov/pubmed/30140323
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