Multiple thioredoxin-mediated routes to detoxify hydroperoxides in Mycobacterium tuberculosis

Jaeger, Timo; Budde, Heike; Flohé, Leopold; Menge, Ulrich; Singh, Mahavir; Trujillo, Madia; Radí, Rafael

doi:10.1016/j.abb.2003.11.021

Cited by 149 publications

(166 citation statements)

References 47 publications

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“…Upon addition of Tpx to the reaction, an approximate 50% increase in NADPH oxidation was observed. TrxR and its combination with Tpx showed NADPH oxidation, which is in agreement with previous reports [5,24]. Individual enzymes did not show any activity except for TrxR, which shows a 90% decrease in the reductase activity as compared to the thioredoxin system.…”

Section: Reductase Activity Of Recombinant Thioredoxin Systemsupporting

confidence: 92%

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Glutathione disulfide and S‐nitrosoglutathione detoxification by Mycobacteriumtuberculosis thioredoxin system

et al. 2009

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a b s t r a c tMycobacterium tuberculosis resides within alveolar macrophages. These phagocytes produce reactive nitrogen and oxygen intermediates to combat the invading pathogens. The macrophage glutathione (GSH) pool reduces nitric oxide (NO) to S-nitrosoglutathione (GSNO). Both glutathione disulfide (GSSG) and GSNO possess mycobactericidal activities in vitro. In this study we demonstrate that M. tuberculosis thioredoxin system, comprises of thioredoxin reductase B2 and thioredoxin C reduces the oxidized form of the intracellular mycothiol (MSSM) and is able to efficiently reduce GSSG and GSNO in vitro. Our study suggests that the thioredoxin system provide a general reduction mechanism to cope with oxidative stress associated with the microbe's metabolism as well as to detoxify xenobiotics produced by the host.

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Section: Reductase Activity Of Recombinant Thioredoxin Systemsupporting

confidence: 92%

“…Thioredoxin systems [5] are key ubiquitous thiol-disulfide oxidoreductases. The thioredoxin system is composed of thioredoxins and thioredoxin reductases, which transfer electrons from NADPH to terminal oxidized substrates and protein disulfides [6].…”

Section: Introductionmentioning

confidence: 99%

Glutathione disulfide and S‐nitrosoglutathione detoxification by Mycobacteriumtuberculosis thioredoxin system

et al. 2009

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“…S. coelicolor) do not synthesize glutathione but in cells they have mycothiol (Newton et al 1996) and their redox regulation is also under control of Trx system. In mycobacteria, it has been confirmed that mycothiol plays important role in detoxification, quenching reactive oxygen and nitrogen metabolites formed in phagocytes during infection and provides reducing equivalents for peroxiredoxins (Shinnick et al 1995;Zhang et al 1999;Jaeger et al 2004). In this way, Trx system is essential for pathogens and helps them survive in host cells.…”

Section: Thioredoxin System Of Selected Pathogens As a Therapeutic Tamentioning

confidence: 99%

Thioredoxin system – a novel therapeutic target

Koháryová¹,

Kollárová²

2015

gpb

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Abstract. Nowadays there are numerous pathogens that have created a resistance to commonly used antibiotics and drugs. Therefore research is focused on finding new therapeutic targets and on determination of their 3D structures that could help in designing new effective substances and inhibitors. Thioredoxin system not only plays a crucial role as thiol/disulfide redox controller, it is also essential for certain organisms as the only system ensuring the redox homeostasis. It is the redox-regulating function, which makes thioredoxin and thioredoxin reductase attractive for scientific research, especially in many studies of diseases caused by redox instability. Thanks to these facts, the proteins of thioredoxin system are suitable candidates for new therapeutic purposes. In this review we summarized the basic features of the thioredoxin system, we justified why the proteins of thioredoxin system are appropriate therapeutical targets and we provided overview of the possibilities of their inhibition by several types of inhibitors.

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“…In the case of Mn 3ϩ -TM-4-PyP, the second order rate constant for its reaction with peroxynitrite was determined previously as 3.7 ϫ 10 6 M Ϫ1 s Ϫ1 at pH 7.4 and 37°C (46). The effect of increasing concentrations of TbcTXNPX on peroxynitrite-mediated Mn 3ϩ -TM-4-PyP oxidation was determined by stopped flow (47). Experiments were performed at 37°C, and the pH was measured at the outlet.…”

Section: Chemicalsmentioning

confidence: 99%

Trypanosoma brucei and Trypanosoma cruzi Tryparedoxin Peroxidases Catalytically Detoxify Peroxynitrite via Oxidation of Fast Reacting Thiols

Trujillo

Budde

Piñeyro³

et al. 2004

Journal of Biological Chemistry

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122

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Macrophage activation is one of the hallmarks observed in trypanosomiasis, and the parasites must cope with the resulting oxidative burden, which includes the production of peroxynitrite, an unusual peroxo-acid that acts as a strong oxidant and trypanocidal molecule. Cytosolic tryparedoxin peroxidase (cTXNPx) has been recently identified as essential for oxidative defense in trypanosomatids. This peroxiredoxin decomposes peroxides using tryparedoxin (TXN) as electron donor, which in turn is reduced by dihydrotrypanothione. In this work, we studied the kinetics of the reaction of peroxynitrite with the different thiol-containing components of the cytosolic tryparedoxin peroxidase system in T. brucei (Tb) and T. cruzi (Tc), namely trypanothione, TXN, and cTXNPx. We found that whereas peroxynitrite reacted with dihydrotrypanothione and TbTXN at moderate rates (7200 and 3500 M ؊1 s ؊1 , respectively, at pH 7.4 and 37°C) and within the range of typical thiols, the second order rate constants for the reaction of peroxynitrite with reduced TbcTXNPx and TccTXNPx were 9 ؋ 10 5 and 7.2 ؋ 10 5 M ؊1 s ؊1 at pH 7.4 and 37°C, respectively. This reactivity was dependent on a highly reactive cTXNPx thiol group identified as cysteine 52. Competition experiments showed that TbcTXNPx inhibited other fast peroxynitrite-mediated processes, such as the oxidation of Mn 3؉ -porphyrins. Moreover, steady-state kinetic studies indicate that peroxynitrite-dependent TbcTXNPx and TccTXNPx oxidation is readily reverted by TXN, supporting that these peroxiredoxins would be not only a preferential target for peroxynitrite reactivity but also be able to act catalytically in peroxynitrite decomposition in vivo.

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Multiple thioredoxin-mediated routes to detoxify hydroperoxides in Mycobacterium tuberculosis

Cited by 149 publications

References 47 publications

Glutathione disulfide and S‐nitrosoglutathione detoxification by Mycobacteriumtuberculosis thioredoxin system

Glutathione disulfide and S‐nitrosoglutathione detoxification by Mycobacteriumtuberculosis thioredoxin system

Thioredoxin system – a novel therapeutic target

Trypanosoma brucei and Trypanosoma cruzi Tryparedoxin Peroxidases Catalytically Detoxify Peroxynitrite via Oxidation of Fast Reacting Thiols

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