ArticlePloS one2013
Isoniazid inhibits the heme-based reactivity of Mycobacterium tuberculosis truncated hemoglobin N.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 32 citations in OpenAlex.
- Common Adverse Reactions and Management Strategies of First-Line Anti-Tuberculosis Drugs.Infection and drug resistance · 2026Review
- Article
- Nitrite Reductase Activity of Ferrous Nitrobindins: A Comparative Study.International journal of molecular sciences · 2023Article
- Strategies of Pathogens to Escape from NO-Based Host Defense.Antioxidants (Basel, Switzerland) · 2022Review
- The Balancing of Peroxynitrite Detoxification between Ferric Heme-Proteins and COAntioxidants (Basel, Switzerland) · 2022Article
- Hydroxylamine-induced oxidation of ferrous nitrobindins.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2022Article
- Mycobacterial and Human Ferrous Nitrobindins: Spectroscopic and Reactivity Properties.International journal of molecular sciences · 2021Article
- Ferric nitrosylated myoglobin catalyzes peroxynitrite scavenging.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2020Article
- Human nitrobindin: the first example of an all-β-barrel ferric heme-protein that catalyzes peroxynitrite detoxification.FEBS open bio · 2018Article
- Regulation of Three Virulence Strategies of Mycobacterium tuberculosis: A Success Story.International journal of molecular sciences · 2018Review
- Peroxynitrite scavenging by Campylobacter jejuni truncated hemoglobin P.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2017Article
- Hydroxylamine-induced oxidation of ferrous carbonylated truncated hemoglobins from Mycobacterium tuberculosis and Campylobacter jejuni is limited by carbon monoxide dissociation.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2017Article
- Isoniazid metabolism and hepatotoxicity.Acta pharmaceutica Sinica. B · 2016Review
- The Mycobacterium tuberculosis Rv2745c plays an important role in responding to redox stress.PloS one · 2014Article
- Nitrosylation mechanisms of Mycobacterium tuberculosis and Campylobacter jejuni truncated hemoglobins N, O, and P.PloS one · 2014Article
- Nitrite-reductase and peroxynitrite isomerization activities of Methanosarcina acetivorans protoglobin.PloS one · 2014Article
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Authors and funding
11 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Isoniazid represents a first-line anti-tuberculosis medication in prevention and treatment. This prodrug is activated by a mycobacterial catalase-peroxidase enzyme called KatG in Mycobacterium tuberculosis), thereby inhibiting the synthesis of mycolic acid, required for the mycobacterial cell wall. Moreover, isoniazid activation by KatG produces some radical species (e.g., nitrogen monoxide), that display anti-mycobacterial activity. Remarkably, the ability of mycobacteria to persist in vivo in the presence of reactive nitrogen and oxygen species implies the presence in these bacteria of (pseudo-)enzymatic detoxification systems, including truncated hemoglobins (trHbs). Here, we report that isoniazid binds reversibly to ferric and ferrous M. tuberculosis trHb type N (or group I; Mt-trHbN(III) and Mt-trHbN(II), respectively) with a simple bimolecular process, which perturbs the heme-based spectroscopic properties. Values of thermodynamic and kinetic parameters for isoniazid binding to Mt-trHbN(III) and Mt-trHbN(II) are K= (1.1 ± 0.1)× 10(-4) M, k on= (5.3 ± 0.6)× 10(3) M(-1) s(-1) and k off= (4.6 ± 0.5)× 10(-1) s(-1); and D= (1.2 ± 0.2)× 10(-3) M, d on= (1.3 ± 0.4)× 10(3) M(-1) s(-1), and d off=1.5 ± 0.4 s(-1), respectively, at pH 7.0 and 20.0°C. Accordingly, isoniazid inhibits competitively azide binding to Mt-trHbN(III) and Mt-trHbN(III)-catalyzed peroxynitrite isomerization. Moreover, isoniazid inhibits Mt-trHbN(II) oxygenation and carbonylation. Although the structure of the Mt-trHbN-isoniazid complex is not available, here we show by docking simulation that isoniazid binding to the heme-Fe atom indeed may take place. These data suggest a direct role of isoniazid to impair fundamental functions of mycobacteria, e.g. scavenging of reactive nitrogen and oxygen species, and metabolism.
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