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Featured researches published by Narimantas Cenas.


Free Radical Biology and Medicine | 1999

Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product

Diana Metodiewa; Anil K. Jaiswal; Narimantas Cenas; Eglé Dičkancaité; Juan Segura-Aguilar

In the last ten years, there has been an important increase in interest in quercetin action as a unique antioxidant, but its putative role in numerous prooxidant effects is also being continually updated. The mechanism underlying this undesirable ability seems to involve its metabolic oxidoreductive activation. Based on the structural properties of quercetin, we have investigated whether its catechol moiety may be the potential tool for revealed toxicity. We demonstrated, with an ESR spin-stabilization technique coupled to conventional spectrophotometry, that o-semiquinone and o-quinone are indeed the products of enzymatically catalyzed oxidative degradation of quercetin. The former radical might serve to facilitate the formation of superoxide and depletion of GSH, which could confer a specificity of its prooxidative action in situ. The observed one-electron reduction of o-quinone may enrich the semiquinone pool, thereby magnifying its effect. The two-electron reduction of quinone can result in constant resupply of quercetin in situ, thereby also modulating another pathway of its known biological activities. We have also tried to see whether the intracellular oxidative degradation of quercetin can be confirmed under the controlled conditions of model monolayer cell cultures. The results are indicative of the intracellular metabolic activation of quercetin to o-quinone, the process which can be partially associated with the observed concentration-dependent cytotoxic effect of quercetin.


Biochimica et Biophysica Acta | 1983

Oxidation of glucose oxidase from Penicillium vitale by one- and two-electron acceptors

J.J. Kulys; Narimantas Cenas

Abstract The steady-state oxidation of glucose oxidase Penicillium vitale by p -quinoids depends on the potential of electron acceptors; log k ox (M −1 ,s −1 ) = 3.2 + 8.4 E 7 0 (V) (pH 7.0, 25°C). Inorganic electron acceptors and organic compounds containing charged groups show a lower reactivity. The rate constant increase in the case of negatively charged acceptors proceeds parallel with the increase in the dissociation rate constant of FAD in the pH range 4–5. A lower reactivity of inorganic complexes and charged organic acceptors is related to the difficulties enountered by the ions penetrating to the enzyme active centre. The results obtained are interpreted in the framework of the outer spherical electron transfer theory. The distance of electron transfer calculated for the oxidation of glucose oxidase by inorganic complexes is equal to 11–13 A at pH 7.0 and approx. 8 A at pH 4.0.


PLOS ONE | 2008

Cell Death by SecTRAPs: Thioredoxin Reductase as a Prooxidant Killer of Cells

Karin Anestål; Stefanie Prast-Nielsen; Narimantas Cenas; Elias S.J. Arnér

Background SecTRAPs (selenium compromised thioredoxin reductase-derived apoptotic proteins) can be formed from the selenoprotein thioredoxin reductase (TrxR) by targeting of its selenocysteine (Sec) residue with electrophiles, or by its removal through C-terminal truncation. SecTRAPs are devoid of thioredoxin reductase activity but can induce rapid cell death in cultured cancer cell lines by a gain of function. Principal Findings Both human and rat SecTRAPs killed human A549 and HeLa cells. The cell death displayed both apoptotic and necrotic features. It did not require novel protein synthesis nor did it show extensive nuclear fragmentation, but it was attenuated by use of caspase inhibitors. The redox active disulfide/dithiol motif in the N-terminal domain of TrxR had to be maintained for manifestation of SecTRAP cytotoxicity. Stopped-flow kinetics showed that NADPH can reduce the FAD moiety in SecTRAPs at similar rates as in native TrxR and purified SecTRAPs could maintain NADPH oxidase activity, which was accelerated by low molecular weight substrates such as juglone. In a cellular context, SecTRAPs triggered extensive formation of reactive oxygen species (ROS) and consequently antioxidants could protect against the cell killing by SecTRAPs. Conclusions We conclude that formation of SecTRAPs could contribute to the cytotoxicity seen upon exposure of cells to electrophilic agents targeting TrxR. SecTRAPs are prooxidant killers of cells, triggering mechanisms beyond those of a mere loss of thioredoxin reductase activity.


Journal of Biological Chemistry | 2004

Interactions of Quinones with Thioredoxin Reductase A CHALLENGE TO THE ANTIOXIDANT ROLE OF THE MAMMALIAN SELENOPROTEIN

Narimantas Cenas; Henrikas Nivinskas; Zilvinas Anusevicius; Jonas Šarlauskas; Florence Lederer; Elias S.J. Arnér

Mammalian thioredoxin reductases (TrxR) are important selenium-dependent antioxidant enzymes. Quinones, a wide group of natural substances, human drugs, and environmental pollutants may act either as TrxR substrates or inhibitors. Here we systematically analyzed the interactions of TrxR with different classes of quinone compounds. We found that TrxR catalyzed mixed single- and two-electron reduction of quinones, involving both the selenium-containing motif and a second redox center, presumably FAD. Compared with other related pyridine nucleotide-disulfide oxidoreductases such as glutathione reductase or trypanothione reductase, the kcat/Km value for quinone reduction by TrxR was about 1 order of magnitude higher, and it was not directly related to the one-electron reduction potential of the quinones. A number of quinones were reduced about as efficiently as the natural substrate thioredoxin. We show that TrxR mainly cycles between the four-electron reduced (EH4) and two-electron reduced (EH2) states in quinone reduction. The redox potential of the EH2/EH4 couple of TrxR calculated according to the Haldane relationship with NADPH/NADP+ was –0.294 V at pH 7.0. Antitumor aziridinylbenzoquinones and daunorubicin were poor substrates and almost inactive as reversible TrxR inhibitors. However, phenanthrene quinone was a potent inhibitor (approximate Ki = 6.3 ± 1 μm). As with other flavoenzymes, quinones could confer superoxide-producing NADPH oxidase activity to mammalian TrxR. A unique feature of this enzyme was, however, the fact that upon selenocysteine-targeted covalent modification, which inactivates its normal activity, reduction of some quinones was not affected, whereas that of others was severely impaired. We conclude that interactions with TrxR may play a considerable role in the complex mechanisms underlying the diverse biological effects of quinones.


Journal of Biological Chemistry | 2006

Interactions of Nitroaromatic Compounds with the Mammalian Selenoprotein Thioredoxin Reductase and the Relation to Induction of Apoptosis in Human Cancer Cells

Narimantas Cenas; Stefanie Prast; Henrikas Nivinskas; Jonas Šarlauskas; Elias S.J. Arnér

Here we described novel interactions of the mammalian selenoprotein thioredoxin reductase (TrxR) with nitroaromatic environmental pollutants and drugs. We found that TrxR could catalyze nitroreductase reactions with either one- or two-electron reduction, using its selenocysteine-containing active site and another redox active center, presumably the FAD. Tetryl and p-dinitrobenzene were the most efficient nitroaromatic substrates with a kcat of 1.8 and 2.8 s–1, respectively, at pH 7.0 and 25 °C using 50 μM NADPH. As a nitroreductase, TrxR cycled between four- and two-electron-reduced states. The one-electron reactions led to superoxide formation as detected by cytochrome c reduction and, interestingly, reductive N-denitration of tetryl or 2,4-dinitrophenyl-N-methylnitramine, resulting in the release of nitrite. Most nitroaromatics were uncompetitive and noncompetitive inhibitors with regard to NADPH and the disulfide substrate 5,5′-dithiobis(2-nitrobenzoic acid), respectively. Tetryl and 4,6-dinitrobenzofuroxan were, however, competitive inhibitors with respect to 5,5′-dithiobis(2-nitrobenzoic acid) and were clearly substrates for the selenolthiol motif of the enzyme. Furthermore, tetryl and 4,6-dinitrobenzofuroxan efficiently inactivated TrxR, likely by alkylation of the selenolthiol motif as in the inhibition of TrxR by 1-chloro-2,4-dinitrobenzene/dinitrochlorobenzene (DNCB) or juglone. The latter compounds were the most efficient inhibitors of TrxR activity in a cellular context. DNCB, juglone, and tetryl were highly cytotoxic and induced caspase-3/7 activation in HeLa cells. Furthermore, DNCB and juglone were potent inducers of apoptosis also in Bcl2 overexpressing HeLa cells or in A549 cells. Based on these findings, we suggested that targeting of intracellular TrxR by alkylating nitroaromatic or quinone compounds may contribute to the induction of apoptosis in exposed human cancer cells.


Methods in Enzymology | 2004

Structure-Activity Relationships in Two-Electron Reduction of Quinones

Narimantas Cenas; Zilvinas Anusevicius; Henrikas Nivinskas; Lina Miseviciene; Jonas Šarlauskas

Publisher Summary This chapter analyzes the structure-activity relationships in two-electron reduction of quinines. Quinones may accept electrons from various flavoenzymes, iron-sulfur proteins and photosynthetic reaction centers. The energetics of the quinine reduction are studied extensively by pulse-radiolysis, electron spin resonance, and electrochemical techniques. The single-electron reduction of quinones by flavoenzyme dehydrogenases-electrontransferases may be treated according to an ‘‘outer-sphere electron transfer’’ model. In general, the reaction rates increase with an increase in quinine single-electron reduction potential. In this chapter, it is demonstrated that multiparameter regression analysis, by using redox potential and several simple structural parameters of quinones, may provide important information on the mechanisms of two-electron enzymatic reduction. In view of the simplicity of the single-electron reduction mechanism and the presumable involvement of single-electron transfers in two-electron reduction, the single-electron reduction of quinones is analyzed. Single-electron reduction of quinones by flavoenzymes is analyzed. The chapter presents the outer-sphere electron transfer model in single-electron reduction of quinones. Structure-activity relationships in single-electron reduction of quinones by NADPH:Cytochrome P-450 reductase and ferredoxin:NADP + reductase are explored. Two-electron reduction of quinones by flavoenzymes is explained in the chapter. The chapter describes the mechanism of two-electron (Hydride) transfer.


Biochimica et Biophysica Acta | 1991

The rotenone-insensitive reduction of quinones and nitrocompounds by mitochondrial NADH:ubiquinone reductase

Daiva Bironaite; Narimantas Cenas; J.J. Kulys

The rotenone-insensitive reduction of quinones and aromatic nitrocompounds by mitochondrial NADH: ubiquinone reductase (complex I, EC 1.6.99.3) has been studied. It was found that these reactions proceed via a mixed one- and two-electron transfer. The logarithms of the bimolecular rate constants of oxidation (TN/Km) are proportional to the one-electron-reduction potentials of oxidizers. The reactivities of nitrocompounds are close to those of quinones. Unlike the reduction of ferricyanide, these reactions are not inhibited by NADH. However, they are inhibited by NAD+ and ADP-ribose, which also act as the mixed-type inhibitors for ferricyanide. TN/Km of quinones and nitrocompounds depend on the NAD+/NADH ratio, but not on NAD+ concentration. They are diminished by the limiting factors of 2.5-3.5 at NAD+/NADH greater than 200. It seems that rotenone-insensitive reduction of quinones and nitrocompounds takes place near the NAD+/NADH and ferricyanide binding site, and the inhibition is caused by induced conformational changes after the binding of NAD+ or ADP-ribose.


Biochimica et Biophysica Acta | 1989

One- and two-electron reduction of quinones by glutathione reductase

Narimantas Cenas; Gelmé A. Rakauskiené; J.J. Kulys

Yeast glutathione reductase (E.C. 1.6.4.2) catalyzes the oxidation of NADPH by p-quinones and ferricyanide with a maximal turnover number (TNmax) of 4-5 s-1.NADP+ stimulates the reaction and the TNmax/Km value of acceptors is reached at NADP+/NADPH greater than or equal to 100. TNmax is increased up to 30-33 s-1. The stimulatory effect of NADP+ may be associated with its complexation with the NADPH-binding site in the reduced enzyme (Kd = 40-60 microM). It is suggested that NADP+ shifts the electron density towards FAD in the two-electron-reduced enzyme and, evidently, changes its one-electron-reduction potentials, while quinones oxidize an equilibrium form of glutathione reductase containing reduced FAD. In the absence of NADP+ the reduction of quinones by glutathione reductase proceeds mainly in a two-electron manner. At NADP+/NADPH = 100 a one-electron reduction makes up 44% of the total process. At pH 6.0-7.0 the reduced forms of naphthoquinones undergo cyclic redox conversions. A hyperbolic dependence exists of the log TN/Km of quinones on their one-electron-reduction potentials.


Iubmb Life | 1997

Toxicity of daunorubicin and naphthoquinones to HL-60 cells: an involvement of oxidative stress.

Eglé Dičkancaité; Narimantas Cenas; Audroné Kalvelyté; Nijolé Serapiniené

Incubation of HL‐60 cells with anthracycline daunorubicin caused an appearance of viable apoptotic, nonviable apoptotic, necrotic (nonviable nonapoptotic) and chromatin‐free (late apoptotic) cells. Both necrotic and apoptotic cell responses were partly prevented by antioxidant N,N′‐diphenyl‐p‐phenylene diamine (DPPD) and iron‐chelating agent, desferrioxamine, suggesting an involvement of activated oxygen species. The comparison of cytotoxicity of daunorubicin and of 5‐hydroxy‐ and 5,8‐dihydroxy‐1,4‐naphthoquinones revealed that at equitoxic concentrations, hydroxynaphthoquinones induced a larger number of necrotic cells in comparison to daunorubicin, a process being partly prevented by DPPD and desferrioxamine. However, we have found that cytotoxicity of daunorubicin was markedly higher in comparison with a series of naphtho‐ and benzoquinones, where an increase of cytotoxicity upon increase in single‐electron reduction potential of quinones (E17) was observed, pointing out to redox cycling as to the main factor of cytotoxicity. This discrepancy could be explained by additional factor(s) of daunorubicin cytotoxicity, e.g. DNA‐intercalation, or selective accumulation of daunorubicin in cell nucleus.


Archives of Biochemistry and Biophysics | 1992

Fungal quinone pigments as oxidizers and inhibitors of mitochondrial NADH:ubiquinone reductase

Daiva Bironaite; Narimantas Cenas; Žilvinas Anusevičius; Alexander Grigorievich Medentsev; Vasilyi K. Akimenko; Sergey A. Usanov

The interaction of fungal quinone pigments bostricoidin, fusarubin, javanicin, and 2-oxyjuglone with mitochondrial NADH:ubiquinone reductase (complex I, EC 1.6.99.3) has been studied. The bimolecular rate constants (turnover number (TN)/Km) of rotenone-insensitive reduction of these compounds are in the range of 1.2 x 10(4)-1.6 x 10(5) M-1s-1. 2-Oxyjuglone acts as inhibitor of NADH:ferricyanide reductase reaction of complex I (KI = 30 microM). All quinone pigments, except javanicin, decrease the TN of reduction of 5,8-dioxy-1,4-naphtoquinone being reduced at its binding site but with significantly lower TN. They do not affect the rotenone-sensitive reduction of ubiquinone-1. The binding of quinone pigments close to the NADH and ferricyanide binding site is suggested. It seems that quinone pigments, especially 2-oxyjuglone, react with complex I faster than it follows from their approximate values of one-electron reduction potential calculated from their reactivities with flavocychrome b2 and adrenodoxin.

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Jonas Šarlauskas

Lithuanian Academy of Sciences

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J.J. Kulys

Lithuanian Academy of Sciences

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Daiva Bironaite

Lithuanian Academy of Sciences

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Eglé Dičkancaité

Lithuanian Academy of Sciences

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John S. Blanchard

Albert Einstein College of Medicine

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Ivonne M. C. M. Rietjens

Wageningen University and Research Centre

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