ArticleProtein science : a publication of the Protein Society2010
Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: catalase, peroxidase, and INH-NADH adduct formation activities.
Article in Protein science : a publication of the Protein Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53 citing papers in PubMed, 123 citations in OpenAlex.
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- Uncovering the structural impact of KatG Ser315 mutations in Mycobacterium tuberculosis via cryo-EM.Protein science : a publication of the Protein Society · 2026Article
- An explainable artificial intelligence framework reveals mutations associated with drug resistance inBiosafety and health · 2025Article
- Comparison of Pyrazinamide with Isoniazid for Their Effects on the Heme Biosynthetic Pathway in Mouse Liver.Metabolites · 2025Article
- Innovative Bedaquiline-Based Delivery Systems for Multidrug-Resistant Tuberculosis Treatment.Infectious disorders drug targets · 2025Review
- Computational analyses of drug resistance mutations in katG and emb complexes in Mycobacterium tuberculosis.Proteins · 2025Article
- Indole N-Linked Hydroperoxyl Adduct of Protein-Derived Cofactor Modulating Catalase-Peroxidase Functions.Angewandte Chemie (International ed. in English) · 2024Article
- Catalase-peroxidase (KatG): a potential frontier in tuberculosis drug development.Critical reviews in biochemistry and molecular biology · 2024Review
- Multi-drug resistant gene mutation analysis inIranian journal of microbiology · 2024Article
- Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistantmBio · 2024Article
- Characterization of a catalase-peroxidase variant (L333V-KatG) identified in an INH-resistantBiochemistry and biophysics reports · 2024Article
- Shared challenges to the control of complex intracellular neglected pathogens.Frontiers in public health · 2024Review
- DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid.Nature communications · 2023Article
- Gated Calcium Ion Channel and Mutation Mechanisms in Multidrug-Resistant Tuberculosis.International journal of molecular sciences · 2023Review
- The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development.Molecular biomedicine · 2022Review
- Whole-genome sequencing ofEpidemiology and infection · 2022Article
- SNPPar: identifying convergent evolution and other homoplasies from microbial whole-genome alignments.Microbial genomics · 2021Article
- Using cryo-EM to understand antimycobacterial resistance in the catalase-peroxidase (KatG) from Mycobacterium tuberculosis.Structure (London, England : 1993) · 2021Article
- Structure-based drug design, synthesis and screening of MmaA1 inhibitors as novel anti-TB agents.Molecular diversity · 2021Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Mycobacterium tuberculosis catalase-peroxidase (KatG) is a bifunctional hemoprotein that has been shown to activate isoniazid (INH), a pro-drug that is integral to frontline antituberculosis treatments. The activated species, presumed to be an isonicotinoyl radical, couples to NAD(+)/NADH forming an isoniazid-NADH adduct that ultimately confers anti-tubercular activity. To better understand the mechanisms of isoniazid activation as well as the origins of KatG-derived INH-resistance, we have compared the catalytic properties (including the ability to form the INH-NADH adduct) of the wild-type enzyme to 23 KatG mutants which have been associated with isoniazid resistance in clinical M. tuberculosis isolates. Neither catalase nor peroxidase activities, the two inherent enzymatic functions of KatG, were found to correlate with isoniazid resistance. Furthermore, catalase function was lost in mutants which lacked the Met-Tyr-Trp crosslink, the biogenic cofactor in KatG which has been previously shown to be integral to this activity. The presence or absence of the crosslink itself, however, was also found to not correlate with INH resistance. The KatG resistance-conferring mutants were then assayed for their ability to generate the INH-NADH adduct in the presence of peroxide (t-BuOOH and H(2)O(2)), superoxide, and no exogenous oxidant (air-only background control). The results demonstrate that residue location plays a critical role in determining INH-resistance mechanisms associated with INH activation; however, different mutations at the same location can produce vastly different reactivities that are oxidant-specific. Furthermore, the data can be interpreted to suggest the presence of a second mechanism of INH-resistance that is not correlated with the formation of the INH-NADH adduct.
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