Thioredoxin reductase as a pathophysiological factor and drug target

Becker, Katja; Gromer, Stephan; Schirmer, R. Heiner; Müller, Sylke

doi:10.1046/j.1432-1327.2000.01703.x

Cited by 350 publications

(239 citation statements)

References 55 publications

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“…Since Plasmodium, like tumor cells, is particularly susceptible to oxidative challenge, the glutathione system and the thioredoxin system ( Fig. 1) represent potential targets for antiparasitic and antitumor drug design (2)(3)(4)(5)(6)(7).…”

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confidence: 99%

The Thioredoxin System of the Malaria Parasite Plasmodium falciparum

Kanzok¹,

Schirmer²,

Türbachova³

et al. 2000

Journal of Biological Chemistry

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235

193

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In most living cells, redox homeostasis is based both on the glutathione and the thioredoxin system. In the malaria parasite Plasmodium falciparum antioxidative proteins represent promising targets for the development of antiparasitic drugs. We cloned and expressed a thioredoxin of P. falciparum (pftrx), and we improved the stable expression of the thioredoxin reductase (PfTrxR) of the parasite by multiple silent mutagenesis. Both proteins were biochemically characterized and compared with the human host thioredoxin system. Intriguingly, the 13-kDa protein PfTrx is a better substrate for human TrxR (K m ‫؍‬ 2 M, k cat ‫؍‬ 3300 min ؊1 ) than for P. falciparum TrxR (K m ‫؍‬ 10.4 M, k cat ‫؍‬ 3100 min ؊1 ). Possessing a midpoint potential of ؊270 mV, PfTrx was found to reduce the disease-related metabolites S-nitrosoglutathione and GSSG. The rate constant k 2 for the reaction between reduced P. falciparum thioredoxin and GSSG was determined to be 0.039 M ؊1 min ؊1 at 25°C and pH 7.4. The k 2 for thioredoxins from man, Drosophila melanogaster, and Escherichia coli was ϳ5 times lower. Our data suggest that GSSG reduction can be supported at a high rate by the TrxR/Trx system in glutathione reductase-deficient cells; this may be relevant for certain stages of the malarial parasite but also for cells containing high [GSSG] of other organisms like dormant forms of Neurospora, glutathione reductasedeficient yeast mutants, or CD4 ؉ lymphocytes of AIDS patients.

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confidence: 99%

The Thioredoxin System of the Malaria Parasite Plasmodium falciparum

Kanzok¹,

Schirmer²,

Türbachova³

et al. 2000

Journal of Biological Chemistry

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235

193

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“…[245] Interestingly, recent research focused on targeting TrxR for cancer treatment. [240,246,247] Both cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms are essential regulators of the redox balance and participate in a variety of functions (e.g. DNA repair, cell proliferation, angiogenesis, transcription).…”

Section: Seleno-enzymesmentioning

confidence: 99%

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

108

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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“…AF is a thiol-reactive organometallic compound that changes the intracellular redox status (Gromer et al, 1998;Becker et al, 2000). As 2 O 3 also interacts with redox enzymes that have thiol groups and depletes intracellular reduced glutathione (GSH) by forming a complex with GSH (Snow, 1992;Scott et al, 1993;Davison et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Auranofin induces apoptosis and when combined with retinoic acid enhances differentiation of acute promyelocytic leukaemia cells in vitro

Kim

Jin

Lee

et al. 2004

British J Pharmacology

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1 Acute promyelocytic leukaemia (APL) is characterized by a block in differentiation at the promyelocyte stage. Here, we describe the effects of auranofin (AF), a coordinated gold compound, on apoptosis and differentiation of APL cells. 2 Nucleosomal DNA fragmentation assay and Hoechst 33342 staining indicated that AF induced apoptosis in APL-derived NB4 cells at low concentrations (0.5-1.0 mM). The AF-induced apoptosis involved caspase-3 activation and specific cleavage of poly-ADP-ribose polymerase. 3 The AF-treated NB4 cells also produced reactive oxygen species (ROS) and cotreatment with Nacetyl-L-cysteine protected the NB4 cells from AF-induced apoptosis. 4 Expression of the CD11b cell surface marker and C/EBPe was increased when the cells were treated for 4 days with 0.3 mM AF and a physiological concentration of all-trans retinoic acid (ATRA, 5 nM). Treatment with AF in combination with ATRA markedly increased the number of cells with differentiated features, such as lobed or multiple nuclei and numerous granules and vacuoles. At these low concentrations, neither AF nor ATRA alone induced significant cell differentiation. 5 These findings suggest not only that AF induces caspase-3-dependent apoptosis via a mechanism involving ROS, but also that the combined treatment with AF and ATRA induces differentiation of NB4 cells. Our results demonstrate a novel characteristic of AF from which an effective drug treatment of APL might be developed.

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Thioredoxin reductase as a pathophysiological factor and drug target

Cited by 350 publications

References 55 publications

The Thioredoxin System of the Malaria Parasite Plasmodium falciparum

The Thioredoxin System of the Malaria Parasite Plasmodium falciparum

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Auranofin induces apoptosis and when combined with retinoic acid enhances differentiation of acute promyelocytic leukaemia cells in vitro

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