quinone reductases

Summary

Summary: NAD(P)H:(quinone acceptor) oxidoreductases. A family that includes three enzymes which are distinguished by their sensitivity to various inhibitors. EC 1.6.99.2 (NAD(P)H DEHYDROGENASE (QUINONE);) is a flavoprotein which reduces various quinones in the presence of NADH or NADPH and is inhibited by dicoumarol. EC 1.6.99.5 (NADH dehydrogenase (quinone)) requires NADH, is inhibited by AMP and 2,4-dinitrophenol but not by dicoumarol or folic acid derivatives. EC 1.6.99.6 (NADPH dehydrogenase (quinone)) requires NADPH and is inhibited by dicoumarol and folic acid derivatives but not by 2,4-dinitrophenol.

Top Publications

  1. Yagi T, Matsuno Yagi A. The proton-translocating NADH-quinone oxidoreductase in the respiratory chain: the secret unlocked. Biochemistry. 2003;42:2266-74 pubmed
  2. Iskander K, Paquet M, Brayton C, Jaiswal A. Deficiency of NRH:quinone oxidoreductase 2 increases susceptibility to 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene-induced skin carcinogenesis. Cancer Res. 2004;64:5925-8 pubmed
    ..The results also suggest that lack of induction of p53, p21, and Bax proteins might contribute to increased sensitivity of NQO2-/- mice skin to benzo(a)pyrene carcinogenicity. ..
  3. Leung S, Gibbons P, Amewu R, Nixon G, Pidathala C, Hong W, et al. Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2). J Med Chem. 2012;55:1844-57 pubmed publisher
    ..falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies. ..
  4. Buryanovskyy L, Fu Y, Boyd M, Ma Y, Hsieh T, Wu J, et al. Crystal structure of quinone reductase 2 in complex with resveratrol. Biochemistry. 2004;43:11417-26 pubmed
  5. Jamieson D, Wilson K, Pridgeon S, Margetts J, Edmondson R, Leung H, et al. NAD(P)H:quinone oxidoreductase 1 and nrh:quinone oxidoreductase 2 activity and expression in bladder and ovarian cancer and lower NRH:quinone oxidoreductase 2 activity associated with an NQO2 exon 3 single-nucleotide polymorphism. Clin Cancer Res. 2007;13:1584-90 pubmed
    ..In contrast, the low level of NQO1 activity and expression relative to other tissues suggests that NQO1-directed therapies would not be appropriate. ..
  6. Jamieson D, Cresti N, Bray J, Sludden J, Griffin M, Hawsawi N, et al. Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy. Pharmacogenet Genomics. 2011;21:808-19 pubmed publisher
    ..This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity. ..
  7. Steuber J, Schmid C, Rufibach M, Dimroth P. Na+ translocation by complex I (NADH:quinone oxidoreductase) of Escherichia coli. Mol Microbiol. 2000;35:428-34 pubmed
    ..With an E. coli mutant deficient in complex I, the Na+ transport activity was low (1-3 nmol mg-1 min-1), and rotenone was without effect. ..
  8. Mohelnikova Duchonova B, Marsakova L, Vrana D, Holcatova I, Ryska M, Smerhovsky Z, et al. Superoxide dismutase and nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase polymorphisms and pancreatic cancer risk. Pancreas. 2011;40:72-8 pubmed publisher
    ..Despite this observation, other populations with different lifestyle(s) may be at risk and should be further studied. ..
  9. Ohnishi T, Nakamaru Ogiso E. Were there any "misassignments" among iron-sulfur clusters N4, N5 and N6b in NADH-quinone oxidoreductase (complex I)?. Biochim Biophys Acta. 2008;1777:703-10 pubmed publisher
    ..Therefore, we believe that we have not made any "misassignment" in our work. ..

More Information

Publications61

  1. Rix U, Hantschel O, Dürnberger G, Remsing Rix L, Planyavsky M, Fernbach N, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110:4055-63 pubmed
    ..4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs. ..
  2. Matsushita K, Ohnishi T, Kaback H. NADH-ubiquinone oxidoreductases of the Escherichia coli aerobic respiratory chain. Biochemistry. 1987;26:7732-7 pubmed
  3. Celli C, Tran N, Knox R, Jaiswal A. NRH:quinone oxidoreductase 2 (NQO2) catalyzes metabolic activation of quinones and anti-tumor drugs. Biochem Pharmacol. 2006;72:366-76 pubmed
    ..These results concluded that NQO2 plays a significant role in the metabolic activation of both quinones and anti-tumor drugs leading to cytotoxicity and cell death. ..
  4. Zhang J, Liu H, Xiao Y, Zhang X, Zhou N. Identification and characterization of catabolic para-nitrophenol 4-monooxygenase and para-benzoquinone reductase from Pseudomonas sp. strain WBC-3. J Bacteriol. 2009;191:2703-10 pubmed publisher
    ..J. Moonen, N. M. Kamerbeek, A. H. Westphal, S. A. Boeren, D. B. Janssen, M. W. Fraaije, and W. J. van Berkel, J. Bacteriol. 190:5190-5198, 2008), suggesting that the genes involved in PNP degradation are physically linked. ..
  5. Hubackova M, Vaclavikova R, Ehrlichova M, Mrhalova M, Kodet R, Kubackova K, et al. Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas. Int J Cancer. 2012;130:338-48 pubmed publisher
    ..004). Our results suggest that NQO2, SOD2 and SOD3 may significantly modify prognosis of breast cancer patients and that their significance should be further characterized. ..
  6. Leung K, Litchfield D, Shilton B. Flavin adenine dinucleotide content of quinone reductase 2: analysis and optimization for structure-function studies. Anal Biochem. 2012;420:84-9 pubmed publisher
    ..This method of purification and reconstitution will help to optimize structural and functional studies of NQO2 and possibly other flavoproteins. ..
  7. Mailliet F, Ferry G, Vella F, Berger S, Coge F, Chomarat P, et al. Characterization of the melatoninergic MT3 binding site on the NRH:quinone oxidoreductase 2 enzyme. Biochem Pharmacol. 2005;71:74-88 pubmed
    ..The compounds described in the present paper are new tools for such a task. ..
  8. Vella F, Ferry G, Delagrange P, Boutin J. NRH:quinone reductase 2: an enzyme of surprises and mysteries. Biochem Pharmacol. 2005;71:1-12 pubmed
    ..Finally QR2 might be implicated in the toxicity, in vivo, of quinones such as menadione. The present commentary attempts to summarize this information and discusses a series of hypotheses. ..
  9. Shiemke A, Arp D, Sayavedra Soto L. Inhibition of membrane-bound methane monooxygenase and ammonia monooxygenase by diphenyliodonium: implications for electron transfer. J Bacteriol. 2004;186:928-37 pubmed
    ..Implications of these data for the electron transfer pathway from the quinone pool to pMMO and AMO are discussed. ..
  10. Theissen U, Hoffmeister M, Grieshaber M, Martin W. Single eubacterial origin of eukaryotic sulfide:quinone oxidoreductase, a mitochondrial enzyme conserved from the early evolution of eukaryotes during anoxic and sulfidic times. Mol Biol Evol. 2003;20:1564-74 pubmed
  11. Asher G, Lotem J, Cohen B, Sachs L, Shaul Y. Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci U S A. 2001;98:1188-93 pubmed
    ..Dicoumarol also reduced the level of p53 in its mutant form in M1 cells. The results indicate that NQO1 plays an important role in regulating p53 functions by inhibiting its degradation. ..
  12. Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci U S A. 2002;99:3099-104 pubmed
    ..The present data on the genetic and pharmacologic regulation of the level of p53 have clinical implications for tumor development and therapy. ..
  13. Heyno E, Alkan N, Fluhr R. A dual role for plant quinone reductases in host-fungus interaction. Physiol Plant. 2013;149:340-53 pubmed publisher
    b>Quinone reductases (QR, EC 1.5.6.2) are flavoproteins that protect organisms from oxidative stress. The function of plant QRs has not as yet been addressed in vivo despite biochemical evidence for their involvement in redox reactions...
  14. Teh J, Yano T, Rubin H. Type II NADH: menaquinone oxidoreductase of Mycobacterium tuberculosis. Infect Disord Drug Targets. 2007;7:169-81 pubmed
    ..In this chapter, we critically review the recent advances in this field, with particular emphasis on NDH-2, and underscore the kinds of research further needed for drug development. ..
  15. Griesbeck C, Schutz M, Schödl T, Bathe S, Nausch L, Mederer N, et al. Mechanism of sulfide-quinone reductase investigated using site-directed mutagenesis and sulfur analysis. Biochemistry. 2002;41:11552-65 pubmed
    ..On the basis of these data, reaction mechanisms for sulfide-dependent reduction and quinone-dependent oxidation of the enzyme and for the formation of polysulfide are proposed. ..
  16. Weinstein E, Yano T, Li L, Avarbock D, Avarbock A, Helm D, et al. Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci U S A. 2005;102:4548-53 pubmed
    ..Several phenothiazines analogs are highly tuberculocidal in vitro, suppress Mtb growth in a mouse model of acute infection, and represent lead compounds that may give rise to a class of selective antibiotics. ..
  17. Nakamaru Ogiso E, Yano T, Yagi T, Ohnishi T. Characterization of the iron-sulfur cluster N7 (N1c) in the subunit NuoG of the proton-translocating NADH-quinone oxidoreductase from Escherichia coli. J Biol Chem. 2005;280:301-7 pubmed
  18. Fu Y, Buryanovskyy L, Zhang Z. Crystal structure of quinone reductase 2 in complex with cancer prodrug CB1954. Biochem Biophys Res Commun. 2005;336:332-8 pubmed
    CB1954 is a cancer pro-drug that can be activated through reduction by Escherichia coli nitro-reductases and quinone reductases. Human quinone reductase 2 is very efficient in the activation of CB1954, approximately 3000 times more ..
  19. AbuKhader M, Heap J, De Matteis C, Kellam B, Doughty S, Minton N, et al. Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex. J Med Chem. 2005;48:7714-9 pubmed
    ..The structure also reveals an unfavorable interaction, therefore suggesting possible avenues for DEPT-tailored engineering studies. ..
  20. Sampaio L. An unexpected effect of 5-MCA-NAT in chick retinal development. Int J Dev Neurosci. 2009;27:511-5 pubmed publisher
  21. Marcia M, Ermler U, Peng G, Michel H. The structure of Aquifex aeolicus sulfide:quinone oxidoreductase, a basis to understand sulfide detoxification and respiration. Proc Natl Acad Sci U S A. 2009;106:9625-30 pubmed publisher
  22. Reybier K, Perio P, Ferry G, Bouajila J, Delagrange P, Boutin J, et al. Insights into the redox cycle of human quinone reductase 2. Free Radic Res. 2011;45:1184-95 pubmed publisher
    ..In conclusion, EPR analysis of QR2 enzyme activity through free radical production enables modulators and effective inhibitors to be distinguished. ..
  23. Winger J, Hantschel O, Superti Furga G, Kuriyan J. The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2). BMC Struct Biol. 2009;9:7 pubmed publisher
    ..Taken together, these studies provide insight into the mechanism of NQO2 inhibition by imatinib, with potential implications for drug design and treatment of chronic myelogenous leukemia in patients. ..
  24. Long D, Iskander K, Gaikwad A, Arin M, Roop D, Knox R, et al. Disruption of dihydronicotinamide riboside:quinone oxidoreductase 2 (NQO2) leads to myeloid hyperplasia of bone marrow and decreased sensitivity to menadione toxicity. J Biol Chem. 2002;277:46131-9 pubmed
    ..The NQO2-null mice are a model for NQO2 deficiency in humans and can be used to determine the role of this enzyme in sensitivities to toxicity and carcinogenesis. ..
  25. Kwiek J, Haystead T, Rudolph J. Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines. Biochemistry. 2004;43:4538-47 pubmed
    ..Our studies shed light on the possible in vivo potency of the quinolines and provide a foundation for future studies aimed at creating more potent QR2 inhibitors and at understanding the physiological significance of QR2. ..
  26. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25:1035-44 pubmed
    ..The data suggest that our approach is a valuable tool for drug discovery. ..
  27. Melo A, Bandeiras T, Teixeira M. New insights into type II NAD(P)H:quinone oxidoreductases. Microbiol Mol Biol Rev. 2004;68:603-16 pubmed
    ..The latter showed that most organisms contain genes that potentially encode NDH-2. An overview of this development is presented, with special emphasis on microbial enzymes and on the identification of three subfamilies of NDH-2. ..
  28. Joseph P, Jaiswal A. A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C. Br J Cancer. 2000;82:1305-11 pubmed
    ..This activity, like NQO1, was inhibited by dicoumarol and immunologically related to NQO1. ..
  29. Fisher N, Warman A, Ward S, Biagini G. Chapter 17 Type II NADH: quinone oxidoreductases of Plasmodium falciparum and Mycobacterium tuberculosis kinetic and high-throughput assays. Methods Enzymol. 2009;456:303-20 pubmed publisher
    ..In addition, owing to the interest in ndhs as potential chemotherapeutic targets, we describe a miniaturized endpoint assay that is validated for high-throughput screening (HTS) of chemical libraries. ..
  30. Calamini B, Santarsiero B, Boutin J, Mesecar A. Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2. Biochem J. 2008;413:81-91 pubmed publisher
    ..These results provide new insights into the binding mechanisms of melatonin and analogues to QR2. ..
  31. Cohen R, Suzuki M, Hammel K. Differential stress-induced regulation of two quinone reductases in the brown rot basidiomycete Gloeophyllum trabeum. Appl Environ Microbiol. 2004;70:324-31 pubmed
    b>Quinone reductases (QRDs) have two important functions in the basidiomycete Gloeophyllum trabeum, which causes brown rot of wood. First, a QRD is required to generate biodegradative hydroxyl radicals via redox cycling between two G...
  32. Pidathala C, Amewu R, Pacorel B, Nixon G, Gibbons P, Hong W, et al. Identification, design and biological evaluation of bisaryl quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2). J Med Chem. 2012;55:1831-43 pubmed publisher
    ..Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress. ..
  33. Sulzenbacher G, Roig Zamboni V, Pagot F, Grisel S, Salomoni A, Valencia C, et al. Structure of Escherichia coli YhdH, a putative quinone oxidoreductase. Acta Crystallogr D Biol Crystallogr. 2004;60:1855-62 pubmed
    ..6 A resolution, respectively. The overall fold of YhdH is very similar to that of alcohol dehydrogenases and quinone reductases despite its low sequence identity...
  34. Yano T, Li L, Weinstein E, Teh J, Rubin H. Steady-state kinetics and inhibitory action of antitubercular phenothiazines on mycobacterium tuberculosis type-II NADH-menaquinone oxidoreductase (NDH-2). J Biol Chem. 2006;281:11456-63 pubmed
    ..Trifluoperazine inhibition is non-competitive for NADH, whereas the inhibition kinetics is found to be uncompetitive in terms of Q2. ..
  35. Price B, Brand M. Proton translocation by the mitochondrial cytochrome b-c1 complex is inhibited by NN'-dicyclohexylcarbodi-imide. Biochem J. 1982;206:419-21 pubmed
    ..The decrease in stoicheiometry is due, not to uncoupling or inhibition of electron transport, but to inhibition of proton translocation. NN'-Dicyclohexylcarbodi-imide thus 'decouples' proton translocation in the cytochrome b-c1 complex. ..
  36. Malik M, Zargar S, Mittal B. Role of NQO1 609C>T and NQO2-3423G>A polymorphisms in susceptibility to gastric cancer in Kashmir valley. DNA Cell Biol. 2011;30:297-303 pubmed publisher
    ..The interaction of NQO1/NQO2 genotypes with high consumption of salted tea, a known risk factor, did not further modulate the risk of GC. In conclusion, NQO1 609C>T polymorphism shows association with GC risk in Kashmir valley. ..
  37. Schrenk D. Impact of dioxin-type induction of drug-metabolizing enzymes on the metabolism of endo- and xenobiotics. Biochem Pharmacol. 1998;55:1155-62 pubmed
    ..The relevance of these observations for humans exposed to dioxin-type inducers is discussed. ..
  38. Hayashi M, Hirai K, Unemoto T. Sequencing and the alignment of structural genes in the nqr operon encoding the Na(+)-translocating NADH-quinone reductase from Vibrio alginolyticus. FEBS Lett. 1995;363:75-7 pubmed
    ..FEBS Lett. 356 (1994) 333-338], the nqr operon was found to be constructed from six consecutive structural genes, where nqr1, nqr3 and nqr6 correspond to the alpha-, gamma-, and beta-subunits, respectively, of the NQR complex...
  39. Lin P, Puhar A, Steuber J. NADH oxidation drives respiratory Na+ transport in mitochondria from Yarrowia lipolytica. Arch Microbiol. 2008;190:471-80 pubmed publisher
    ..Our study indicates that energy conversion by mitochondria does not exclusively rely on the proton motive force but may benefit from the electrochemical Na+ gradient established by complex I. ..
  40. Bertsova Y, Bogachev A. The origin of the sodium-dependent NADH oxidation by the respiratory chain of Klebsiella pneumoniae. FEBS Lett. 2004;563:207-12 pubmed
    ..It is concluded that the NQR-type enzyme, not the NDH-1-type enzyme, catalyzes sodium-dependent NADH oxidation in K. pneumoniae. ..
  41. Iskander K, Li J, Han S, Zheng B, Jaiswal A. NQO1 and NQO2 regulation of humoral immunity and autoimmunity. J Biol Chem. 2006;281:30917-24 pubmed
    ..The results led to the conclusion that NQO1 and NQO2 are endogenous factors in the regulation of immune response and autoimmunity...
  42. Boussard M, Truche S, Rousseau Rojas A, Briss S, Descamps S, Droual M, et al. New ligands at the melatonin binding site MT(3). Eur J Med Chem. 2006;41:306-20 pubmed
  43. Sørensen M, Jensen B, Poulsen H, Deng X, Tygstrup N, Dalhoff K, et al. Effects of a Brussels sprouts extract on oxidative DNA damage and metabolising enzymes in rat liver. Food Chem Toxicol. 2001;39:533-40 pubmed
    ..However, the observed increase in oxidative DNA damage raises the question of whether greatly increased ingestion of cruciferous vegetables is beneficial. ..
  44. Xu L, Wain J, Miller D, Thurston S, Su L, Lynch T, et al. The NAD(P)H:quinone oxidoreductase 1 gene polymorphism and lung cancer: differential susceptibility based on smoking behavior. Cancer Epidemiol Biomarkers Prev. 2001;10:303-9 pubmed
    ..Our results support the concept that differential susceptibility to lung cancer is a function of both an inheritable trait in NQO1 metabolism and individual smoking characteristics. ..
  45. Brito J, Bandeiras T, Teixeira M, Vonrhein C, Archer M. Crystallisation and preliminary structure determination of a NADH: quinone oxidoreductase from the extremophile Acidianus ambivalens. Biochim Biophys Acta. 2006;1764:842-5 pubmed
    ..0. NDH-2 was solubilised with the detergent n-dodecyl-beta-d-maltoside and crystallised using ammonium phosphate as precipitant. The structure was solved by MIRAS using Pt and I derivatives...
  46. Teeter L, Petersen D, Nebert D, Kuo M. Murine mdr-1, mdr-2, and mdr-3 gene expression: no coinduction with the Cyp1a-1 and Nmo-1 genes in liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin. DNA Cell Biol. 1991;10:433-41 pubmed
    ..Therefore, we conclude that any effects that TCDD might have on MDR expression must be substantially different from TCDD effects on genes known to be induced via the Ah receptor. ..
  47. Oxenkrug G, Bachurin S, Prakhie I, Zefirov N. Quinone reductase 2 and antidepressant effect of melatonin derivatives. Ann N Y Acad Sci. 2010;1199:121-4 pubmed publisher
    ..Our results suggest that the modulation of QR2/MT3 might contribute to mechanism(s) of antidepressant effect. New antidepressants might be searched among the agonists of QR2/MT3. ..
  48. Laso N, Mas S, Lafuente M, Llobet J, Molina R, Ballesta A, et al. Induction of NAD(P)H quinone oxidoreductase by vegetables widely consumed in Catalonia, Spain. Nutr Cancer. 2005;52:49-58 pubmed
    ..These results are very similar to those described for vegetables consumed in the United States, with the exception of calcot, which is common in Catalonia but is not grown or consumed widely in the United States. ..
  49. Hayashi M, Hirai K, Unemoto T. Cloning of the Na(+)-translocating NADH-quinone reductase gene from the marine bacterium Vibrio alginolyticus and the expression of the beta-subunit in Escherichia coli. FEBS Lett. 1994;356:330-2 pubmed
    ..Among the subclones selected by probe C, the expression of the beta-subunit as a gene product was detected in Escherichia coli membranes by activity staining and Western blotting...
  50. Nishio K, Nakamura S, Sekido Y, Niwa T, Hamajima N. Associations between disease risk and eight polymorphisms adopted for genotype announcements at Nagoya University Hospital. Nagoya J Med Sci. 2004;67:51-8 pubmed
    ..Since showed a potential for widespread use in health checkups, the information on the above polymorphisms seems worth documenting. Although there have been no complaints from the participants to date, careful treatments are requested. ..
  51. Steuber J, Rufibach M, Fritz G, Neese F, Dimroth P. Inactivation of the Na+-translocating NADH:ubiquinone oxidoreductase from Vibrio alginolyticus by reactive oxygen species. Eur J Biochem. 2002;269:1287-92 pubmed
    ..alginolyticus. It is shown that the [2Fe-2S] cluster previously assigned to the Na+-NQR originates from the succinate dehydrogenase or the related enzyme fumarate reductase. ..
  52. Konsue N, Ioannides C. Differential response of four human livers to modulation of phase II enzyme systems by the chemopreventive phytochemical phenethyl isothiocyanate. Mol Nutr Food Res. 2010;54:1477-85 pubmed publisher
    ..These studies illustrate that there are very pronounced differences in the response of human liver to PEITC, indicating that the chemopreventive effect of isothiocyanates may not be manifested in all individuals. ..