Selenium-Catalyzed Reduction of Hydroperoxides in Chemistry and Biology

Among the chalcogens, selenium is the key element for catalyzed H2O2 reduction. In organic synthesis, catalytic amounts of organo mono- and di-selenides are largely used in different classes of oxidations, in which H2O2 alone is poorly efficient. Biological hydroperoxide metabolism is dominated by peroxidases and thioredoxin reductases, which balance hydroperoxide challenge and contribute to redox regulation. When their selenocysteine is replaced by cysteine, the cellular antioxidant defense system is impaired. Finally, classes of organoselenides have been synthesized with the aim of mimicking the biological strategy of glutathione peroxidases, but their therapeutic application has so far been limited. Moreover, their therapeutic use may be doubted, because H2O2 is not only toxic but also serves as an important messenger. Therefore, over-optimization of H2O2 reduction may lead to unexpected disturbances of metabolic regulation. Common to all these systems is the nucleophilic attack of selenium to one oxygen of the peroxide bond promoting its disruption. In this contribution, we revisit selected examples from chemistry and biology, and, by using results from accurate quantum mechanical modelling, we provide an accurate unified picture of selenium’s capacity of reducing hydroperoxides. There is clear evidence that the selenoenzymes remain superior in terms of catalytic efficiency.

Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity

Nitroaromatic compounds (ArNO2) maintain their importance in relation to industrial processes, environmental pollution, and pharmaceutical application. The manifestation of toxicity/therapeutic action of nitroaromatics may involve their single- or two-electron reduction performed by various flavoenzymes and/or their physiological redox partners, metalloproteins. The pivotal and still incompletely resolved questions in this area are the identification and characterization of the specific enzymes that are involved in the bioreduction of ArNO2 and the establishment of their contribution to cytotoxic/therapeutic action of nitroaromatics. This review addresses the following topics: (i) the intrinsic redox properties of ArNO2, in particular, the energetics of their single- and two-electron reduction in aqueous medium; (ii) the mechanisms and structure-activity relationships of reduction in ArNO2 by flavoenzymes of different groups, dehydrogenases-electrontransferases (NADPH:cytochrome P-450 reductase, ferredoxin:NADP(H) oxidoreductase and their analogs), mammalian NAD(P)H:quinone oxidoreductase, bacterial nitroreductases, and disulfide reductases of different origin (glutathione, trypanothione, and thioredoxin reductases, lipoamide dehydrogenase), and (iii) the relationships between the enzymatic reactivity of compounds and their activity in mammalian cells, bacteria, and parasites.

Micro RNAs in Regulation of Cellular Redox Homeostasis

In living cells Reactive Oxygen Species (ROS) participate in intra- and inter-cellular signaling and all cells contain specific systems that guard redox homeostasis. These systems contain both enzymes which may produce ROS such as NADPH-dependent and other oxidases or nitric oxide synthases, and ROS-neutralizing enzymes such as catalase, peroxiredoxins, thioredoxins, thioredoxin reductases, glutathione reductases, and many others. Most of the genes coding for these enzymes contain sequences targeted by micro RNAs (miRNAs), which are components of RNA-induced silencing complexes and play important roles in inhibiting translation of their targeted messenger RNAs (mRNAs). In this review we describe miRNAs that directly target and can influence enzymes responsible for scavenging of ROS and their possible role in cellular redox homeostasis. Regulation of antioxidant enzymes aims to adjust cells to survive in unstable oxidative environments; however, sometimes seemingly paradoxical phenomena appear where oxidative stress induces an increase in the levels of miRNAs which target genes which are supposed to neutralize ROS and therefore would be expected to decrease antioxidant levels. Here we show examples of such cellular behaviors and discuss the possible roles of miRNAs in redox regulatory circuits and further cell responses to stress.

Juvenile Selenium Deficiency Impairs Cognition, Sensorimotor Gating, and Energy Homeostasis in Mice

Selenium (Se) is an essential micronutrient of critical importance to mammalian life. Its biological effects are primarily mediated via co-translational incorporation into selenoproteins, as the unique amino acid, selenocysteine. These proteins play fundamental roles in redox signaling and includes the glutathione peroxidases and thioredoxin reductases. Environmental distribution of Se varies considerably worldwide, with concomitant effects on Se status in humans and animals. Dietary Se intake within a narrow range optimizes the activity of Se-dependent antioxidant enzymes, whereas both Se-deficiency and Se-excess can adversely impact health. Se-deficiency affects a significant proportion of the world's population, with hypothyroidism, cardiomyopathy, reduced immunity, and impaired cognition being common symptoms. Although relatively less prevalent, Se-excess can also have detrimental consequences and has been implicated in promoting both metabolic and neurodegenerative disease in humans. Herein, we sought to comprehensively assess the developmental effects of both Se-deficiency and Se-excess on a battery of neurobehavioral and metabolic tests in mice. Se-deficiency elicited deficits in cognition, altered sensorimotor gating, and increased adiposity, while Se-excess was surprisingly beneficial.

Unexpected diversity of ferredoxin-dependent thioredoxin reductases in cyanobacteria

Thioredoxin reductases control the redox state of thioredoxins (Trxs)—ubiquitous proteins that regulate a spectrum of enzymes by dithiol-disulfide exchange reactions. In most organisms, Trx is reduced by NADPH via a thioredoxin reductase flavoenzyme (NTR), but in oxygenic photosynthetic organisms, this function can also be performed by an iron-sulfur ferredoxin (Fdx)-dependent thioredoxin reductase (FTR) that links light to metabolic regulation. We have recently found that some cyanobacteria, such as the thylakoid-less Gloeobacter and the ocean-dwelling green oxyphotobacterium Prochlorococcus, lack NTR and FTR but contain a thioredoxin reductase flavoenzyme (formerly tentatively called deeply-rooted thioredoxin reductase or DTR), whose electron donor remained undefined. Here we demonstrate that Fdx functions in this capacity and report the crystallographic structure of the transient complex between the plant-type Fdx1 and the thioredoxin reductase flavoenzyme from Gloeobacter violaceus. Thereby, our data demonstrate that this cyanobacterial enzyme belongs to the Fdx flavin-thioredoxin reductase (FFTR) family, originally described in the anaerobic bacterium Clostridium pasteurianum. Accordingly, the enzyme hitherto termed DTR is renamed FFTR. Our experiments further show that the redox sensitive peptide CP12 is modulated in vitro by the FFTR/Trx system, demonstrating that FFTR functionally substitutes for FTR in light-linked enzyme regulation in Gloeobacter. Altogether, we demonstrate the FFTR is spread within the cyanobacteria phylum and propose that, by substituting for FTR, it connects the reduction of target proteins to photosynthesis. Besides, the results indicate that FFTR acquisition constitutes a mechanism of evolutionary adaptation in marine phytoplankton such as Prochlorococcus that live in low-iron environments.

Repurposing Auranofin and Evaluation of a New Gold(I) Compound for the Search of Treatment of Human and Cattle Parasitic Diseases: From Protozoa to Helminth Infections

Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura®) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-β-d-glucopyranose 2,3,4,6-tetraacetato-S-derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites—protozoans, trematodes, and nematodes—was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic Leishmania donovani amastigotes and adult filarial and trematode worms.

From Selenium to Selenoproteins and their Role - Minireview

Selenium (SE) is an essential micronutrient fulfilling a number of biological roles, being integrated as selenocysteine in the primary structure of certain selenoproteins. The Selenocysteine is synthesized and inserted into proteins during the translational process of the RNAm by a mechanism which involves converting a stop codon for certain proteins into a meaningful codon. Only 25 genes encoding selenocysteine-incorporating proteins have been identified in the human genome. The selenoprotein families including glutathione peroxidase, iodothyronine deiodinase and thioredoxin reductases are known as enzymes engaged in redox processes. The selenoprotein P (SEPP1) is a hepatokine produced by the liver, an extracellular glycoprotein, which is not part of these families. The purpose of this Article is to present the form of distribution of selenium and its physiological role in the body.

Expression of Thioredoxin/Thioredoxin Reductase System Genes in Aphid-Challenged Maize Seedlings

Thioredoxins (Trxs) and thioredoxin reductases (TrxRs) encompass a highly complex network involved in sustaining thiol-based redox homeostasis in plant tissues. The purpose of the study was to gain a new insight into transcriptional reprogramming of the several genes involved in functioning of Trx/TrxR system in maize (Zea mays L.) seedlings, exposed to the bird cherry-oat aphid (Rhopalosiphum padi L.) or the rose-grass aphid (Metopolophium dirhodum Walk.) infestation. The biotests were performed on two maize genotypes (susceptible Złota Karłowa and relatively resistant Waza). The application of real-time qRT-PCR technique allowed to identify a molecular mechanism triggered in more resistant maize plants, linked to upregulation of thioredoxins-encoding genes (Trx-f, Trx-h, Trx-m, Trx-x) and thioredoxin reductase genes (Ftr1, Trxr2). Significant enhancement of TrxR activity in aphid-infested Waza seedlings was also demonstrated. Furthermore, we used an electrical penetration graph (EPG) recordings of M. dirhodum stylet activities in seedlings of the two studied maize varieties. Duration of phloem phase (E1 and E2 models) of rose-grass aphids was about three times longer while feeding in Waza plants, compared to Złota Karłowa cv. The role of activation of Trx/TrxR system in maintaining redox balance and counteracting oxidative-induced damages of macromolecules in aphid-stressed maize plants is discussed.

Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity

Selenium (Se) homeostasis is tightly related to carbohydrate and lipid metabolism, but its possible roles in obesity development and in adipocyte metabolism are unclear. The objective of the present study is to review the current data on Se status in obesity and to discuss the interference between Se and selenoprotein metabolism in adipocyte physiology and obesity pathogenesis. The overview and meta-analysis of the studies on blood Se and selenoprotein P (SELENOP) levels, as well as glutathione peroxidase (GPX) activity in obese subjects, have yielded heterogenous and even conflicting results. Laboratory studies demonstrate that Se may modulate preadipocyte proliferation and adipogenic differentiation, and also interfere with insulin signaling, and regulate lipolysis. Knockout models have demonstrated that the selenoprotein machinery, including endoplasmic reticulum-resident selenoproteins together with GPXs and thioredoxin reductases (TXNRDs), are tightly related to adipocyte development and functioning. In conclusion, Se and selenoproteins appear to play an essential role in adipose tissue physiology, although human data are inconsistent. Taken together, these findings do not support the utility of Se supplementation to prevent or alleviate obesity in humans. Further human and laboratory studies are required to elucidate associations between Se metabolism and obesity.