Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carcinogenicity of the phenolic food antioxidant butylated hydroxyanisole may be related to its oxidative biotransformation in vivo. In order to determine the ability of BHA, 2-tert-butyl(1,4)hydroquinone (TBHQ) and 2-tert-butyl(1,4)paraquinone (TBQ) to induce oxidative DNA damage, biological inactivation of single-stranded bacteriophage phi X-174 DNA, as well as induction of 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in dG by these compounds was studied in vitro, in the presence and absence of peroxidases. Both test systems showed that BHA and TBQ (probably due to lack of reductase activity in vitro) were not capable of inducting oxidative DNA damage. TBHQ, however, appeared to be a strong inactivator of phage DNA as well as a potent inducer of 8-oxodG formation. Addition of radical scavengers showed that this damage was due to formation of superoxide anion, hydrogen peroxide and hydroxyl radicals. Addition of iron chelators and metal ions showed that the one-electron oxidations of TBHQ via the semiquinone radical into TBQ are toxic via the formation of oxygen radicals and are not directly due to the hydroquinone itself or the formation of semiquinone radicals. Although peroxidation of TBHQ by prostaglandin H synthase (PHS) is indicated to result in a superoxide anion burst, this is not accompanied by an increase in oxidative DNA damage in vitro. This might be due to the use of hydrogen peroxide as a substrate by PHS itself, consequently resulting in less formation of hydroxyl radicals. Oxidation of TBHQ by lipoxygenases showed that no semiquinone radicals or oxygen radicals were formed, probably due to a two-electron oxidation of TBHQ directly into TBQ. The present results indicate that metabolic activation of BHA yielding reactive oxygen species may induce a carcinogenic potential, since the BHA metabolite TBHQ, appeared to be a strong inducer of oxidative DNA damage.
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PMID:The role of prostaglandin H synthase-mediated metabolism in the induction of oxidative DNA damage by BHA metabolites. 833 Mar 42

Electron-transfer flavoprotein:rhodoquinone oxidoreductase (ETF-RO) was purified to homogeneity from anaerobic mitochondria of the parasitic nematode, Ascaris suum. The enzyme has a subunit molecular mass of 64.5 kDa and is similar in many respects to the electron-transfer flavoprotein:ubiquinone oxidoreductase (ETF-UO) characterized in mammalian tissues. EPR spectroscopy of the purified enzyme revealed signals at g = 2.076, 1,936, and 1.883, arising from an iron-sulfur center, as well as signals attributable to a flavin semiquinone. Potentiometric titration on the enzyme with dithionite yielded an oxidation-reduction midpoint potential (Em) for the iron-sulfur center of +25 mV at pH 7.4. The reduction of flavin occurred in two distinct steps, with a flavin semiquinone radical detected as an intermediate. The Em values for the two steps in the complete reduction of flavin were +15 mV and -9 mV, respectively. Physiologically, the ascarid ETF-RO accepts electrons from a low potential quinone, rhodoquinone, and functions in a direction opposite to that of the ETF-UO. Incubations of A. suum submitochondrial particles with NADH, 2-methylcrotonyl-CoA, purified A. suum electron-transfer flavoprotein and 2-methyl branched-chain enoyl-CoA reductase resulted in significant 2-methylbutyryl-CoA formation, which was inhibited by both rotenone and antisera to the purified ETF-RO. Quinone extraction of the submitchondrial particles with dry pentane resulted in almost the complete loss of 2-MBCoA formation by the system. However, the reincorporation of rhodoquinone, but not ubiquinone restored over 50% of the NADH-dependent 2-MBCoA formation.
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PMID:Purification and characterization of electron-transfer flavoprotein: rhodoquinone oxidoreductase from anaerobic mitochondria of the adult parasitic nematode, Ascaris suum. 837 93

The reaction mechanism of a 1,4-benzoquinone reductase from the wood-rotting basidiomycete Phanerochaete chrysosporium was investigated. The native, oxidized, FMN-containing enzyme was reduced quantitatively by NADH and the resulting reduced enzyme was reoxidized in the presence of one equivalent of 2,6-di-methoxy-1,4-benzoquinone (DMBQ). The stoichiometry of NADH oxidation versus DMBQ reduction is 1:1. The enzyme catalyzes the reduction of quinones to hydroquinones by a ping-pong steady-state mechanism. However, inhibition is observed at low NADH concentrations. Quinone products derived from the autooxidation of the unstable compounds 1,2,4-trihydroxybenzene and 5-chloro-2,3,4-trihydroxybenzene also appear to be substrates for the quinone reductase. The enzyme reduces the one-electron acceptors ferricyanide and ferricytochrome c (Cc3+) with rates of 58.4 and 0.08%, respectively, compared to DMBQ. The stoichiometry of NADH oxidation versus ferricyanide reduction is 1:2. In the presence of quinones the rates of Cc3+ and ferricyanide reduction are increased, owing to the nonenzymatic reduction of these acceptors by enzyme-generated hydroquinone products. Dicumarol and Cibacron blue are competitive inhibitors with respect to NADH, with Ki values of 2.1 and 0.30 microM, respectively. Reconstitution of the apoprotein with FMN yields a fully active enzyme at an FMN-to-protein ratio of 2:1, suggesting that the flavin content of the enzyme is two molecules of FMN per dimer.
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PMID:1,4-Benzoquinone reductase from basidiomycete Phanerochaete chrysosporium: spectral and kinetic analysis. 866 Jun 80

A FAD and [4Fe-4S]cluster-containing enzyme from Clostridium aminobutyricum catalyses the reversible dehydration of 4-hydroxybutyryl-CoA to crotonyl-CoA which involves the cleavage of an unactivated C-H bond at the beta-carbon. Transient oxidation of the substrate to an enoxy radical by FAD might facilitate the removal of this beta-proton, whereas no function could be attributed to the [4Fe-4S]cluster. In this paper the organic radical, which is formed by partial reduction of the enzyme with dithionite, was characterised as the neutral flavin semiquinone by EPR spectroscopy in H2O and D2O. The rapid electron-spin relaxation of the flavin semiquinone suggested a magnetic interaction with the [4Fe-4S]cluster. In order to obtain highly resolved information about nuclear spins in the vicinity of this paramagnetic centre, ENDOR spectroscopy was applied. The spectra were compared with those of the neutral semiquinone radicals of ferredoxin-NADP reductase and flavodoxin as well as with that of the anionic semiquinone radical of cholesterol oxidase. All ENDOR spectra showed strong couplings to the 8-methyl protons and to H-6 of the flavin. On addition of the substrates to the corresponding enzymes, the electron density changed significantly only at the 8-position. It decreased in the case of cholesterol oxidase and ferredoxin-NADP reductase, whereas an increase was observed with 4-hydroxybutyryl-CoA dehydratase. The results indicate an interaction of 4-hydroxybutyryl-CoA with the flavin as required by the proposed mechanism. Furthermore, the shift of electron density towards the benzoid ring of FAD in the dehydratase might be due to the location of the [4Fe-4S]cluster next to the 8-position as known from structurally characterised iron-sulfur flavoproteins.
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PMID:Electron-nuclear double resonance spectroscopy investigation of 4-hydroxybutyryl-CoA dehydratase from Clostridium aminobutyricum: comparison with other flavin radical enzymes. 937 80

In view of the ubiquitous role of the thioredoxin/thioredoxin reductase (TRX/TR) system in living cells, the interaction of Arabidopsis thaliana NADPH-thioredoxin reductase (EC 1.6.4.5) with quinones, an important class of redox cycling and alkylating xenobiotics, was studied. The steady-state reactions of A. thaliana TR with thioredoxin (TRX) and reaction product NADP+ inhibition patterns were in agreement with a proposed model of E. coli enzyme (B.W. Lennon, C.H. Williams, Jr., Biochemistry, vol. 35 (1996), pp. 4704-4712), that involved enzyme cycling between four- and two-electron reduced forms with FAD being reduced. Quinone reduction by TR proceeded via a mixed single- and two-electron transfer, the percentage of single-electron flux being equal to 12-16%. Bimolecular rate constants of quinone reduction (kcat/km) and reaction catalytic constants (kcat) increased upon an increase in quinone single-electron reduction potential. E(1)7. In several cases, the kcat of quinone reduction exceeded kcat of TRX reduction, suggesting that quinones intercepted electron flux from TR to TRX. Incubation of reduced TR with alkylating quinones resulted in a rapid loss of TRX-reductase activity, while quinone reduction rate was unchanged. In TRX-reductase and quinone reductase reactions of TR, NADP+ exhibited different inhibition patterns. These data point out that FAD and not the catalytic disulfide of TR is responsible for quinone reduction, and that quinones may oxidize FADH2 before it reduces catalytic disulfide. Most probably, quinones may oxidize the two-electron reduced form of TR, and the enzyme may cycle between two-electron reduced and oxidized forms in this reaction. The relatively high rate of quinone reduction by A. thaliana thioredoxin reductase accompanied by their redox cycling, confers pro-oxidant properties to this antioxidant enzyme. These factors make plant TR an attractive target for redox active and alkylating pesticide action.
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PMID:Interaction of quinones with Arabidopsis thaliana thioredoxin reductase. 954 49

Alkylating agents have been used to treat cancer since the 1940s. Quinone-containing alkylating agents represent a class of drugs called "bioreductive alkylating agents." These drugs require reduction of the quinone moiety for activation of their alkylating substituents. Despite active research in this area, mitomycin C is the only bioreductive alkylating agent approved for general use. The "enzyme-directed" approach to bioreductive drug development involves identification of reductases which are overexpressed in tumors when compared to uninvolved tissues. Bioreductive drugs which are substrates for these reductases should be selectively toxic to tumors with high reductase levels. NAD(P)H:quinone oxidoreductase (NQO1, DT-diaphorase, EC 1.6.99.2) is a two-electron reductase found primarily in the cytosol. NQO1 has received considerable attention because of the high levels of this enzyme in tumors particularly in tumors of the lung, colon and breast. In this review, the current state of research on quinone-containing alkylating agents is discussed with the focus on NQO1-directed bioreductive drug development. Recent structure-activity studies on indolequinones, benzoquinones and other novel quinones are reviewed, and the status of drugs which have been studied in clinical trials is discussed. Finally, the limitations and possible future directions in this research area are presented.
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PMID:Mechanisms of action of quinone-containing alkylating agents. I: NQO1-directed drug development. 1087 93

The metabolism of quinone-containing antitumor agents involves enzymatic reduction of the quinone by one or two electrons. This reduction results in the formation of the semiquinone or the hydroquinone of the anticancer drug. The consequence of these enzymatic reductions is that the semiquinone yields its extra electron to oxygen with the formation of superoxide radical anion and the original quinone. This reduction by a reductase followed by oxidation by molecular oxygen (dioxygen) is known as redox-cycling and continues until the system becomes anaerobic. In the case of a two electron reduction, the hydroquinone could become stable, and as such, excreted by the organism in a detoxification pathway. In some cases such as aziridine quinones, the hydroquinone can be oxidized by one electron at a time resulting in the production of superoxide, the semiquinone and the parental quinone. Quinone anticancer agents upon reduction can also set up an equilibrium between the hydroquinone, the parental quinone and the semiquinone which results in a long-lived semiquinone. Depending on the compound, aziridine quinones, for example, this equilibrium is long lasting thus allowing for the detection of the semiquinone under aerobic conditions. This phenomenon is known as comproportionation-disporportionation equilibrium. The series of reviews in this Special Issue address the consequences of bioreduction of quinone alkylators used in the treatment of cancer. In this particular review we are interested in describing the phenomenon of redox-cycling, how it is measured, and the biological consequences of the presence of the semiquinone and the oxygen radicals generated.
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PMID:The metabolism of quinone-containing alkylating agents: free radical production and measurement. 1087 94

Quinone based bioreductive drugs have, potentially, a very versatile use in cancer chemotherapy. They can be activated by DT-diaphorase and hence can be used to target tumour types rich in this (O2)-independent reductase enzyme. Small molecular modifications can substantially reduce specificity for DT-diaphorase and under these circumstances the quinones become much less toxic in air but retain their potent cytotoxic effects under hypoxic conditions. Our understanding of the reductive (bio) chemistry of indolequinones, in particular, has subsequently allowed us to develop a platform technology where almost any therapeutic entity can potentially be delivered, selectively, to hypoxic tumours. Antiangiogenic approaches are currently receiving a substantial amount of attention and this review brings their development into context in view of the hypoxia dependence for neovascularization. Lastly, the use of bioreductive drugs when combined with hypoxia-mediated gene therapy is described. Such an approach provides a unique dual level of specificity for targeting hypoxic tumours and potentially can provide substantial therapeutic benefit.
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PMID:Antiangiogenic, bioreductive and gene therapy approaches to the treatment of hypoxic tumours. 1205 10

Catechol-containing antioxidants are able to protect against lipid peroxidation by nonenzymatic scavenging of free radicals with their catechol moiety. During their antioxidant activity, catechol oxidation products such as semiquinone radicals and quinones are formed. These oxidation products of 4-methylcatechol inactivate the GSH-dependent protection against lipid peroxidation and the calcium sequestration in liver microsomes. This effect is probably due to arylation by oxidation products of 4-methylcatechol of free thiol groups of the enzymes responsible for the GSH-dependent protection and calcium sequestration, i.e. the free radical reductase and calcium ATPase. It is concluded that a catechol-containing antioxidant might shift radical damage from lipid peroxidation to sulfhydryl arylation.
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PMID:Oxidative damage shifts from lipid peroxidation to thiol arylation by catechol-containing antioxidants. 1217 95

Anthracycline antibiotics, including adriamycin (ADM), are widely used to treat various human cancers, but their clinical use has been limited because of their cardiotoxicity. ADM is especially toxic to heart tissue. The mechanisms responsible for the cardiotoxic effect of ADM have been very/extremely controversial. This review focuses on the participation of free radicals generated by ADM in the cardiotoxic effect. ADM is reduced to a semiquinone radical species by microsomal NADPH-P450 reductase and mitochondrial NADH dehydrogenase. In the presence of oxygen, the reductive semiquinone radical species produces superoxide and hydroxyl radicals. Generally, lipid peroxidation proceeds by mediating the redox of iron. ADM extracts iron from ferritin to form ADM-Fe3+, which causes lipid peroxidation of membranes. These events may lead to disturbance of the membrane structure and dysfunction of mitochondria. However, superoxide dismutase and hydroxyl radical scavengers have little effect on lipid peroxidation induced by ADM-Fe3+. Alternatively, ADM is oxidatively activated by peroxidases to convert to an oxidative semiquinone radical, which participates in inactivation of mitochondrial enzymes or including succinate dehydrogenase and creatine kinase. Here, we discuss the activation of ADM and the role of reductive and oxidative ADM semiquinone radicals in the cardiotoxic effect of this antibiotic.
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PMID:[Free radicals mediate cardiac toxicity induced by adriamycin]. 1457 31


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