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Narimantas Cenas - One of the best experts on this subject based on the ideXlab platform.
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interactions of Quinones with thioredoxin reductase a challenge to the antioxidant role of the mammalian selenoprotein
Journal of Biological Chemistry, 2004Co-Authors: Narimantas Cenas, Jonas Šarlauskas, Zilvinas Anusevicius, Henrikas Nivinskas, Florence Lederer, Elias S J ArnerAbstract:Abstract 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.
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mechanism of reduction of Quinones by trypanosoma congolense trypanothione reductase
Biochemistry, 1994Co-Authors: David Arscott, Narimantas Cenas, Charles H. Williams, J S BlanchardAbstract:A number of Quinones were analyzed as substrates for trypanothione reductase from Trypanosoma congolense, an enzyme responsible for the protection of trypanosomes against oxidative stress. Using NADPH as substrate, the maximal rate of the steady-state reaction at pH 7.5 was between 24 and 1.6 s-1 for 11 Quinone substrates. The biomolecular steady-state rate constants for Quinone reduction, V/Km, ranged from 240 to 1.9 x 10(5) M-1 s-1, and their logarithms exhibited a hyperbolic dependence on the one-electron-reduction potentials of the Quinone substrate. The addition of NADP+ stimulated these rates, with V/Km values increasing with an increasing NADP+/NADPH ratio. The results of alkylation of the cysteine residue in the two-electron-reduced enzyme by iodoacetamide indicate that these residues are not primarily involved in the reduction of these Quinones. Single-electron reduction of benzoQuinone constitutes 40% of the total electron transfer from NADPH to Quinone in the absence of NADP+, and increases to 80% at NADP+/NADPH ratios greater than 10. These steady-state results were confirmed in pre-steady-state rapid reaction experiments. The rate of reduced enzyme oxidation by 1,4-benzoQuinone is approximately 100 times faster in the presence of NADP+ than in its absence. The reactivities of various pyridine nucleotide liganded forms of EH2 for Quinone reduction are presumably affected by the electron density at FAD. We suggest that one-electron reduction of Quinones occurs at a site distinct from the two active sites involved in hydride ion transfer and disulfide reduction.
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mechanism of reduction of Quinones by trypanosoma congolense trypanothione reductase
Biochemistry, 1994Co-Authors: David Arscott, Narimantas Cenas, Charles H. Williams, John S BlanchardAbstract:A number of Quinones were analyzed as substrates for trypanothione reductase from Trypanosoma congolense, an enzyme responsible for the protection of trypanosomes against oxidative stress. Using NADPH as substrate, the maximal rate of the steady-state reaction at pH 7.5 was between 24 and 1.6 s -1 for 11 Quinone substrates. The biomolecular steady-state rate constants for Quinone reduction, V/K m , ranged from 240 to 1.9×10 5 M -1 s -1 , and their logarithms exhibited a hyperbolic dependence on the one-electron-reduction potentials of the Quinone substrate. The addition of NADP + stimulated these rates, with V/K m values increasing with an increasing NADP + /NADPH ratio
Kazumasa Wakamatsu - One of the best experts on this subject based on the ideXlab platform.
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Tyrosinase-Catalyzed Oxidation of the Leukoderma-Inducing Agent Raspberry Ketone Produces (E)-4-(3-Oxo-1-butenyl)-1,2-benzoQuinone: Implications for Melanocyte Toxicity.
Chemical Research in Toxicology, 2017Co-Authors: Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa WakamatsuAbstract:The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-Quinones. The results of this study demonstrate that the oxidation of RK by mushroom tyrosinase rapidly produces 4-(3-oxobutyl)-1,2-benzoQuinone (RK-Quinone), which is converted within 10–20 min to (E)-4-(3-oxo-1-butenyl)-1,2-benzoQuinone (DBL-Quinone). These Quinones were identified as their corresponding catechols after reduction by ascorbic acid. RK-Quinone and DBL-Quinone quantitatively bind to the small thio...
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Tyrosinase-Catalyzed Oxidation of the Leukoderma-Inducing Agent Raspberry Ketone Produces (E)‑4-(3-Oxo-1-butenyl)-1,2-benzoQuinone: Implications for Melanocyte Toxicity
2017Co-Authors: Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa WakamatsuAbstract:The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-Quinones. The results of this study demonstrate that the oxidation of RK by mushroom tyrosinase rapidly produces 4-(3-oxobutyl)-1,2-benzoQuinone (RK-Quinone), which is converted within 10–20 min to (E)-4-(3-oxo-1-butenyl)-1,2-benzoQuinone (DBL-Quinone). These Quinones were identified as their corresponding catechols after reduction by ascorbic acid. RK-Quinone and DBL-Quinone quantitatively bind to the small thiol N-acetyl-l-cysteine to form thiol adducts and can also bind to the thiol protein bovine serum albumin through its cysteinyl residue. DBL-Quinone is more reactive than RK-Quinone, as judged by their half-lives (6.2 min vs 10.5 min, respectively), and decays rapidly to form an oligomeric pigment (RK-oligomer). The RK-oligomer can oxidize GSH to GSSG with a concomitant production of hydrogen peroxide, indicating its pro-oxidant activity, similar to that of the RD-oligomer. These results suggest that RK is cytotoxic to melanocytes through the binding of RK-derived Quinones to thiol proteins and the pro-oxidant activity of the RK-oligomer
David Arscott - One of the best experts on this subject based on the ideXlab platform.
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mechanism of reduction of Quinones by trypanosoma congolense trypanothione reductase
Biochemistry, 1994Co-Authors: David Arscott, Narimantas Cenas, Charles H. Williams, J S BlanchardAbstract:A number of Quinones were analyzed as substrates for trypanothione reductase from Trypanosoma congolense, an enzyme responsible for the protection of trypanosomes against oxidative stress. Using NADPH as substrate, the maximal rate of the steady-state reaction at pH 7.5 was between 24 and 1.6 s-1 for 11 Quinone substrates. The biomolecular steady-state rate constants for Quinone reduction, V/Km, ranged from 240 to 1.9 x 10(5) M-1 s-1, and their logarithms exhibited a hyperbolic dependence on the one-electron-reduction potentials of the Quinone substrate. The addition of NADP+ stimulated these rates, with V/Km values increasing with an increasing NADP+/NADPH ratio. The results of alkylation of the cysteine residue in the two-electron-reduced enzyme by iodoacetamide indicate that these residues are not primarily involved in the reduction of these Quinones. Single-electron reduction of benzoQuinone constitutes 40% of the total electron transfer from NADPH to Quinone in the absence of NADP+, and increases to 80% at NADP+/NADPH ratios greater than 10. These steady-state results were confirmed in pre-steady-state rapid reaction experiments. The rate of reduced enzyme oxidation by 1,4-benzoQuinone is approximately 100 times faster in the presence of NADP+ than in its absence. The reactivities of various pyridine nucleotide liganded forms of EH2 for Quinone reduction are presumably affected by the electron density at FAD. We suggest that one-electron reduction of Quinones occurs at a site distinct from the two active sites involved in hydride ion transfer and disulfide reduction.
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mechanism of reduction of Quinones by trypanosoma congolense trypanothione reductase
Biochemistry, 1994Co-Authors: David Arscott, Narimantas Cenas, Charles H. Williams, John S BlanchardAbstract:A number of Quinones were analyzed as substrates for trypanothione reductase from Trypanosoma congolense, an enzyme responsible for the protection of trypanosomes against oxidative stress. Using NADPH as substrate, the maximal rate of the steady-state reaction at pH 7.5 was between 24 and 1.6 s -1 for 11 Quinone substrates. The biomolecular steady-state rate constants for Quinone reduction, V/K m , ranged from 240 to 1.9×10 5 M -1 s -1 , and their logarithms exhibited a hyperbolic dependence on the one-electron-reduction potentials of the Quinone substrate. The addition of NADP + stimulated these rates, with V/K m values increasing with an increasing NADP + /NADPH ratio
Charles H. Williams - One of the best experts on this subject based on the ideXlab platform.
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mechanism of reduction of Quinones by trypanosoma congolense trypanothione reductase
Biochemistry, 1994Co-Authors: David Arscott, Narimantas Cenas, Charles H. Williams, J S BlanchardAbstract:A number of Quinones were analyzed as substrates for trypanothione reductase from Trypanosoma congolense, an enzyme responsible for the protection of trypanosomes against oxidative stress. Using NADPH as substrate, the maximal rate of the steady-state reaction at pH 7.5 was between 24 and 1.6 s-1 for 11 Quinone substrates. The biomolecular steady-state rate constants for Quinone reduction, V/Km, ranged from 240 to 1.9 x 10(5) M-1 s-1, and their logarithms exhibited a hyperbolic dependence on the one-electron-reduction potentials of the Quinone substrate. The addition of NADP+ stimulated these rates, with V/Km values increasing with an increasing NADP+/NADPH ratio. The results of alkylation of the cysteine residue in the two-electron-reduced enzyme by iodoacetamide indicate that these residues are not primarily involved in the reduction of these Quinones. Single-electron reduction of benzoQuinone constitutes 40% of the total electron transfer from NADPH to Quinone in the absence of NADP+, and increases to 80% at NADP+/NADPH ratios greater than 10. These steady-state results were confirmed in pre-steady-state rapid reaction experiments. The rate of reduced enzyme oxidation by 1,4-benzoQuinone is approximately 100 times faster in the presence of NADP+ than in its absence. The reactivities of various pyridine nucleotide liganded forms of EH2 for Quinone reduction are presumably affected by the electron density at FAD. We suggest that one-electron reduction of Quinones occurs at a site distinct from the two active sites involved in hydride ion transfer and disulfide reduction.
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mechanism of reduction of Quinones by trypanosoma congolense trypanothione reductase
Biochemistry, 1994Co-Authors: David Arscott, Narimantas Cenas, Charles H. Williams, John S BlanchardAbstract:A number of Quinones were analyzed as substrates for trypanothione reductase from Trypanosoma congolense, an enzyme responsible for the protection of trypanosomes against oxidative stress. Using NADPH as substrate, the maximal rate of the steady-state reaction at pH 7.5 was between 24 and 1.6 s -1 for 11 Quinone substrates. The biomolecular steady-state rate constants for Quinone reduction, V/K m , ranged from 240 to 1.9×10 5 M -1 s -1 , and their logarithms exhibited a hyperbolic dependence on the one-electron-reduction potentials of the Quinone substrate. The addition of NADP + stimulated these rates, with V/K m values increasing with an increasing NADP + /NADPH ratio
Shosuke Ito - One of the best experts on this subject based on the ideXlab platform.
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Tyrosinase-Catalyzed Oxidation of the Leukoderma-Inducing Agent Raspberry Ketone Produces (E)-4-(3-Oxo-1-butenyl)-1,2-benzoQuinone: Implications for Melanocyte Toxicity.
Chemical Research in Toxicology, 2017Co-Authors: Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa WakamatsuAbstract:The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-Quinones. The results of this study demonstrate that the oxidation of RK by mushroom tyrosinase rapidly produces 4-(3-oxobutyl)-1,2-benzoQuinone (RK-Quinone), which is converted within 10–20 min to (E)-4-(3-oxo-1-butenyl)-1,2-benzoQuinone (DBL-Quinone). These Quinones were identified as their corresponding catechols after reduction by ascorbic acid. RK-Quinone and DBL-Quinone quantitatively bind to the small thio...
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Tyrosinase-Catalyzed Oxidation of the Leukoderma-Inducing Agent Raspberry Ketone Produces (E)‑4-(3-Oxo-1-butenyl)-1,2-benzoQuinone: Implications for Melanocyte Toxicity
2017Co-Authors: Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa WakamatsuAbstract:The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-Quinones. The results of this study demonstrate that the oxidation of RK by mushroom tyrosinase rapidly produces 4-(3-oxobutyl)-1,2-benzoQuinone (RK-Quinone), which is converted within 10–20 min to (E)-4-(3-oxo-1-butenyl)-1,2-benzoQuinone (DBL-Quinone). These Quinones were identified as their corresponding catechols after reduction by ascorbic acid. RK-Quinone and DBL-Quinone quantitatively bind to the small thiol N-acetyl-l-cysteine to form thiol adducts and can also bind to the thiol protein bovine serum albumin through its cysteinyl residue. DBL-Quinone is more reactive than RK-Quinone, as judged by their half-lives (6.2 min vs 10.5 min, respectively), and decays rapidly to form an oligomeric pigment (RK-oligomer). The RK-oligomer can oxidize GSH to GSSG with a concomitant production of hydrogen peroxide, indicating its pro-oxidant activity, similar to that of the RD-oligomer. These results suggest that RK is cytotoxic to melanocytes through the binding of RK-derived Quinones to thiol proteins and the pro-oxidant activity of the RK-oligomer