The Design of Gold-Based, Mitochondria-Targeted Chemotherapeutics

2008 ◽  
Vol 61 (9) ◽  
pp. 661 ◽  
Author(s):  
Susan J. Berners-Price ◽  
Aleksandra Filipovska
Keyword(s):  
Redox Regulation ◽  
Thioredoxin Reductase ◽  
Central Place ◽  
Tumour Cells ◽  
Selective Toxicity ◽  
Phosphine Complexes ◽  
Thioredoxin System ◽  
New Strategy ◽  
Recent Developments ◽  
Targeted Chemotherapeutics

Recent developments in understanding the central place of mitochondria as regulators of programmed cell death have stimulated enormous interest in using them as targets for cancer chemotherapy. To overcome drug resistance and the lack of selectivity of cancer drugs in differentiating between normal and tumour cells, many strategies have been described in recent literature, including the use of delocalized lipophilic cations that selectively accumulate in tumour-cell mitochondria. Thioredoxin reductase, an enzyme involved in redox regulation and cell growth, has also emerged recently as an attractive drug target. Here we discuss the rationale for the design of lipophilic, cationic Au(i) phosphine complexes that are targeted to mitochondria of tumour cells and have potent and selective anticancer activity for cancer cells but not for normal cells. Our discovery that the thioredoxin system may be a critical target responsible for the selective toxicity provides a new strategy in the development of mitochondria-targeted chemotherapeutics.

scholarly journals Crystal Structure of the Apo-Form of NADPH-Dependent Thioredoxin Reductase from a Methane-Producing Archaeon

Antioxidants ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 166 ◽  
Author(s):  
Rubén Buey ◽  
Ruth Schmitz ◽  
Bob Buchanan ◽  
Monica Balsera
Keyword(s):  
Crystal Structure ◽  
Redox Regulation ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Thioredoxin Reductase ◽  
Binding Pocket ◽  
Major Protein ◽  
Exchange Reactions ◽  
Functional Sites ◽  
Structural And Functional Properties ◽  
Thioredoxin System

The redox regulation of proteins via reversible dithiol/disulfide exchange reactions involves the thioredoxin system, which is composed of a reductant, a thioredoxin reductase (TR), and thioredoxin (Trx). In the pyridine nucleotide-dependent Trx reduction pathway, reducing equivalents, typically from reduced nicotinamide adenine dinucleotide phosphate (NADPH), are transferred from NADPH-TR (NTR) to Trx and, in turn, to target proteins, thus resulting in the reversible modification of the structural and functional properties of the targets. NTR enzymes contain three functional sites: an NADPH binding pocket, a non-covalently bound flavin cofactor, and a redox-active disulfide in the form of CxxC. With the aim of increasing our knowledge of the thioredoxin system in archaea, we here report the high-resolution crystal structure of NTR from the methane-generating organism Methanosarcina mazei strain Gö1 (MmNTR) at 2.6 Å resolution. Based on the crystals presently described, MmNTR assumes an overall fold that is nearly identical to the archetypal fold of authentic NTRs; however, surprisingly, we observed no electron density for flavin adenine dinucleotide (FAD) despite the well-defined and conserved FAD-binding cavity in the folded module. Remarkably, the dimers of the apo-protein within the crystal were different from those observed by small angle X-ray scattering (SAXS) for the holo-protein, suggesting that the binding of the flavin cofactor does not require major protein structural rearrangements. Rather, binding results in the stabilization of essential parts of the structure, such as those involved in dimer stabilization. Altogether, this structure represents the example of an apo-form of an NTR that yields important insight into the effects of the cofactor on protein folding.

scholarly journals Chloroplast thioredoxin systems: prospects for improving photosynthesis

2017 ◽  
Vol 372 (1730) ◽  
pp. 20160474 ◽  
Author(s):  
Lauri Nikkanen ◽  
Jouni Toivola ◽  
Manuel Guinea Diaz ◽  
Eevi Rintamäki
Keyword(s):  
Stress Responses ◽  
Redox Regulation ◽  
Carbon Fixation ◽  
Thioredoxin Reductase ◽  
Photosynthetic Performance ◽  
Fine Tuning ◽  
Chloroplast Proteins ◽  
Environmental Light ◽  
Thioredoxin System ◽  
And Function

Thioredoxins (TRXs) are protein oxidoreductases that control the structure and function of cellular proteins by cleavage of a disulphide bond between the side chains of two cysteine residues. Oxidized thioredoxins are reactivated by thioredoxin reductases (TR) and a TR-dependent reduction of TRXs is called a thioredoxin system. Thiol-based redox regulation is an especially important mechanism to control chloroplast proteins involved in biogenesis, in regulation of light harvesting and distribution of light energy between photosystems, in photosynthetic carbon fixation and other biosynthetic pathways, and in stress responses of plants. Of the two plant plastid thioredoxin systems, the ferredoxin-dependent system relays reducing equivalents from photosystem I via ferredoxin and ferredoxin-thioredoxin reductase (FTR) to chloroplast proteins, while NADPH-dependent thioredoxin reductase (NTRC) forms a complete thioredoxin system including both reductase and thioredoxin domains in a single polypeptide. Chloroplast thioredoxins transmit environmental light signals to biochemical reactions, which allows fine tuning of photosynthetic processes in response to changing environmental conditions. In this paper we focus on the recent reports on specificity and networking of chloroplast thioredoxin systems and evaluate the prospect of improving photosynthetic performance by modifying the activity of thiol regulators in plants.This article is part of the themed issue ‘Enhancing photosynthesis in crop plants: targets for improvement'.

scholarly journals Mammalian thioredoxin reductase 1: roles in redox homoeostasis and characterization of cellular targets

2010 ◽  
Vol 430 (2) ◽  
pp. 285-293 ◽  
Author(s):  
Anton A. Turanov ◽  
Sebastian Kehr ◽  
Stefano M. Marino ◽  
Min-Hyuk Yoo ◽  
Bradley A. Carlson ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Thioredoxin Reductase ◽  
In Vitro Assays ◽  
Mouse Serum ◽  
Main Function ◽  
Major Pathway ◽  
Thioredoxin System

The classical Trx (thioredoxin) system, composed of TR (Trx reductase), Trx and NADPH, defines a major pathway of cellular thiol-based redox regulation. Three TRs have been identified in mammals: (i) cytosolic TR1, (ii) mitochondrial TR3 and (iii) testes-specific TGR (Trx-glutathione reductase). All three are selenocysteine-containing enzymes with broad substrate specificity in in vitro assays, but which protein substrates are targeted by TRs in vivo is not well understood. In the present study, we used a mechanism-based approach to characterize the molecular targets of TR1. Cytosolic Trx1 was the major target identified in rat and mouse liver, as well as in rat brain and mouse serum. The results suggest that the main function of TR1 is to reduce Trx1. We also found that TR1-based affinity resins provide a convenient tool for specific isolation of Trxs from a variety of biological samples. To better assess the role of TRs in redox homoeostasis, we comparatively analysed TR1- and TR3-knockdown cells. Although cells deficient in TR1 were particularly sensitive to diamide, TR3-knockdown cells were more sensitive to hydrogen peroxide. To further examine the TR1–Trx1 redox pair, we used mice with a liver-specific knockout of selenocysteine tRNA. In this model, selenocysteine insertion into TR1 was blocked, but the truncated form of this protein was not detected. Instead, TR1 and TR3 levels were decreased in the knockout samples. Diminished hepatic TR1 function was associated with elevated Trx1 levels, but this protein was mostly in the oxidized state. Overall, this study provides evidence for the key role of the TR1–Trx1 pair in redox homoeostasis.

scholarly journals Antioxidant Activities and Selenogene Transcription in the European Sea Bass (Dicentrarchus labrax) Liver Depend, in a Non-linear Manner, on the Se/Hg Molar Ratio of the Feeds

2021 ◽  
Author(s):  
Marinelle Espino ◽  
Harkaitz Eguiraun ◽  
Oihane Diaz de Cerio ◽  
José Antonio Carrero ◽  
Nestor Etxebarria ◽  
...  
Keyword(s):  
Antioxidant Activities ◽  
Dicentrarchus Labrax ◽  
Thioredoxin Reductase ◽  
Sea Bass ◽  
Molar Ratio ◽  
Antioxidant Systems ◽  
European Sea Bass ◽  
Thioredoxin System ◽  
Non Linear ◽  
Linear Manner

AbstractFeeding 3.9 and 6.7 mg Hg/kg (Se/Hg molar ratios of 0.8 and 0.4, respectively) for 14 days negatively affected Dicentrarchus labrax growth and total DNTB- and thioredoxin-reductase (TrxR) activities and the transcription of four redox genes (txn1, gpx1, txnrd3, and txnrd2) in the liver, but a diet with 0.5 mg Hg/kg (Se/Hg molar ratio 6.6) slightly increased both reductase activities and the transcription of txn1, gpx1, and txnrd2. Feeding 6.7 mg Hg/kg for 53 days downregulated the genes of the thioredoxin system (txn1, txnrd3, and txnrd2) but upregulated gpx1, confirming the previously proposed complementarity among the antioxidant systems. Substitution of 20% of the feed by thawed white fish (hake) slightly counteracted the negative effects of Hg. The effects were not statistically significant and were dependent, in a non-linear manner, on the Se/Hg molar ratio of the feed but not on its Hg concentration. These results stress the need to consider the Se/Hg molar ratio of the feed/food when evaluating the toxicity of Hg.

scholarly journals New Insights into the Potential of Endogenous Redox Systems in Wheat Bread Dough

Antioxidants ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 190 ◽  
Author(s):  
Nicolas Navrot ◽  
Rikke Buhl Holstborg ◽  
Per Hägglund ◽  
Inge Povlsen ◽  
Birte Svensson
Keyword(s):  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Thioredoxin Reductase ◽  
Heat Stability ◽  
Wheat Bread ◽  
Enzymatic System ◽  
Redox Systems ◽  
Bread Dough ◽  
Seed Formation ◽  
Protein Substrates ◽  
Thioredoxin System

Various redox compounds are known to influence the structure of the gluten network in bread dough, and hence its strength. The cereal thioredoxin system (NTS), composed of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent thioredoxin reductase (NTR) and thioredoxin (Trx), is a major reducing enzymatic system that is involved in seed formation and germination. NTS is a particularly interesting tool for food processing due to its heat stability and its broad range of protein substrates. We show here that barley NTS is capable of remodeling the gluten network and weakening bread dough. Furthermore, functional wheat Trx that is present in the dough can be recruited by the addition of recombinant barley NTR, resulting in dough weakening. These results confirm the potential of NTS, especially NTR, as a useful tool in baking for weakening strong doughs, or in flat product baking.

scholarly journals Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin – thioredoxin system. 1. Understanding commonalities and differences among cell types

2017 ◽  
Author(s):  
Gianluca Selvaggio ◽  
Pedro M. B. M. Coelho ◽  
Armindo Salvador
Keyword(s):  
Cell Lines ◽  
Thioredoxin Reductase ◽  
Cell Types ◽  
Cell Physiology ◽  
Related Factor ◽  
Similar Response ◽  
Redox Biology ◽  
Analytical Approximations ◽  
Thioredoxin System ◽  
Reduction Capacity

AbstractThe system (PTTRS) formed by typical 2-Cys peroxiredoxins (Prx), thioredoxin (Trx), Trx reductase (TrxR), and sulfiredoxin (Srx) is central in antioxidant protection and redox signaling in the cytoplasm of eukaryotic cells. Understanding how the PTTRS integrates these functions requires tracing phenotypes to molecular properties, which is non-trivial. Here we analyze this problem based on a model that captures the PTTRS’ conserved features. We have mapped the conditions that generate each distinct response to H2O2 supply rates (νsup), and estimated the parameters for thirteen human cell types and for Saccharomyces cerevisiae. The resulting composition-to-phenotype map yielded the following experimentally testable predictions. The PTTRS permits many distinct responses including ultra-sensitivity and hysteresis. However, nearly all tumor cell lines showed a similar response characterized by limited Trx-S- depletion and a substantial but self-limited gradual accumulation of hyperoxidized Prx at high νsup. This similarity ensues from strong correlations between the TrxR, Srx and Prx activities over cell lines, which contribute to maintain the Prx-SS reduction capacity in slight excess over the maximal steady state Prx-SS production. In turn, in erythrocytes, hepatocytes and HepG2 cells high νsup depletes Trx-S- and oxidizes Prx mainly to Prx-SS. In all nucleated human cells the Prx-SS reduction capacity defined a threshold separating two different regimes. At sub-threshold νsup cytoplasmic H2O2 is determined by Prx, nM-range and spatially localized, whereas at supra-threshold νsup it is determined by much less active alternative sinks and μM-range throughout the cytoplasm. The yeast shows a distinct response where the Prx Tsa1 accumulates in sulfenate form at high νsup. This is mainly due to an exceptional stability of Tsa1’s sulfenate.The implications of these findings for thiol redox regulation and cell physiology are discussed. All estimates were thoroughly documented and provided, together with analytical approximations for system properties, as a resource for quantitative redox biology.AbbreviationsASK1, apoptosis signal-regulating kinase 1; Cat, catalase; GSH, glutathione; GPx1, glutathione peroxidase 1; Grx, glutaredoxin; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2-related factor 2; Prx, typical 2-Cys peroxiredoxin; PTTRS, peroxiredoxin / thioredoxin / thioredoxin reductase system; Srx, sulfiredoxin; Trx, thioredoxin; TrxR, thioredoxin reductase.

scholarly journals Selective Toxicity of NSC73306 in MDR1-Positive Cells as a New Strategy to Circumvent Multidrug Resistance in Cancer

2006 ◽  
Vol 66 (9) ◽  
pp. 4808-4815 ◽  
Author(s):  
Joseph A. Ludwig ◽  
Gergely Szakács ◽  
Scott E. Martin ◽  
Benjamin F. Chu ◽  
Carol Cardarelli ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Selective Toxicity ◽  
New Strategy
Sign in / Sign up

Export Citation Format

Share Document