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Modeling the Structural Origins of Drug Resistance to Isoniazid via key Mutations in Mycobacterium tuberculosis Catalase-Peroxidase, KatG

Matthew W. Marney, Robert P. Metzger, David Hecht, Faramarz Valafar
doi: https://doi.org/10.1101/230482
Matthew W. Marney
aDepartment of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030
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Robert P. Metzger
aDepartment of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030
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David Hecht
aDepartment of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030
bDepartment of Chemistry, Southwestern College, Chula Vista, CA 91910
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Faramarz Valafar
cBiomedical Informatics Research Center, San Diego State University, San Diego, CA 92182-7720
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Abstract

WHO reported 10.4 million new tuberculosis (TB) cases and 1.8 million deaths in 2015, making M. tuberculosis the most successful human pathogen with highest mortality among infectious diseases.[1,2] Drug-resistant TB is a major threat to global TB control.[2,3] Recently Torres et al. [4] identified 14 novel substitutions in M. tuberculosis-KatG (the enzyme associated with resistance to isoniazid—an important first-line anti-TB drug) and demonstrated that 12 of the 14 can cause INH-resistance in M. smegmatis. This study presents an in silico structure-based analysis of these 14 amino acid substitutions using homology models and x-ray crystal structures (when available) in M. tuberculosis. Our models demonstrate that several of these mutations cluster around three openings in the KatG tertiary structure which appear to initiate channels to the heme group at the catalytic center of the enzyme. We studied the effects of these mutations on the tertiary structure of KatG, focusing on conformational changes in the three channels in the protein structure. Our results suggest that the 14 novel mutations sufficiently restrict one or more of these access channels, thus potentially preventing INH from reaching the catalytic heme. These observations provide valuable insights into the structure-based origins of INH resistance and provide testable hypotheses for future experimental studies.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 07, 2017.
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Modeling the Structural Origins of Drug Resistance to Isoniazid via key Mutations in Mycobacterium tuberculosis Catalase-Peroxidase, KatG
Matthew W. Marney, Robert P. Metzger, David Hecht, Faramarz Valafar
bioRxiv 230482; doi: https://doi.org/10.1101/230482
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Modeling the Structural Origins of Drug Resistance to Isoniazid via key Mutations in Mycobacterium tuberculosis Catalase-Peroxidase, KatG
Matthew W. Marney, Robert P. Metzger, David Hecht, Faramarz Valafar
bioRxiv 230482; doi: https://doi.org/10.1101/230482

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