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Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol,

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Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595, and Proteomics Facility, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037
Cite this: Biochemistry 2004, 43, 36, 11417–11426
Publication Date (Web):August 17, 2004
https://doi.org/10.1021/bi049162o
Copyright © 2004 American Chemical Society

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    Abstract

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    Resveratrol has been shown to have chemopreventive, cardioprotective, and antiaging properties. Here, we report that resveratrol is a potent inhibitor of quinone reductase 2 (QR2) activity in vitro with a dissociation constant of 35 nM and show that it specifically binds to the deep active-site cleft of QR2 using high-resolution structural analysis. All three resveratrol hydroxyl groups form hydrogen bonds with amino acids from QR2, anchoring a flat resveratrol molecule in parallel with the isoalloxazine ring of FAD. The unique active-site pocket in QR2 could potentially bind other natural polyphenols such as flavonoids, as proven by the high affinity exhibited by quercetin toward QR2. K562 cells with QR2 expression suppressed by RNAi showed similar properties as resveratrol-treated cells in their resistance to quinone toxicity. Furthermore, the QR2 knockdown K562 cells exhibit increased antioxidant and detoxification enzyme expression and reduced proliferation rates. These observations could imply that the chemopreventive and cardioprotective properties of resveratrol are possibly the results of QR2 activity inhibition, which in turn, up-regulates the expression of cellular antioxidant enzymes and cellular resistance to oxidative stress.

     This work was supported in part by National Institute of Health Grant R21 CA104424.

     The atomic coordinates and structure factors (PDB code 1SG0) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

    §

     New York Medical College.

     The Burnham Institute.

    *

     To whom correspondence should be addressed. Telephone:  914-594-4728. Fax:  914-594-4058. E-mail:  [email protected].

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    12. Sandra E. Pineda-Sanabria, Ian M. Robertson, and Brian D. Sykes . Structure of trans-Resveratrol in Complex with the Cardiac Regulatory Protein Troponin C. Biochemistry 2011, 50 (8) , 1309-1320. https://doi.org/10.1021/bi101985j
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    44. Tze-chen Hsieh, Hsiao Hsiang Chao, Joseph M. Wu. Control of DNA structure and function by phytochemicals/DNA interaction: Resveratrol/piceatannol induces Cu2+-independent, cleavage of supercoiled plasmid DNA. Free Radical Biology and Medicine 2020, 147 , 212-219. https://doi.org/10.1016/j.freeradbiomed.2019.12.034
    45. Jacob G. Kraus, Peter Koulen. Resveratrol Directly Controls the Activity of Neuronal Ryanodine Receptors at the Single-Channel Level. Molecular Neurobiology 2020, 57 (1) , 422-434. https://doi.org/10.1007/s12035-019-01705-7
    46. Amirhossein Davoodvandi, Roxana Sahebnasagh, Omid Mardanshah, Zatollah Asemi, Majid Nejati, Mohammad K. Shahrzad, Hamid R. Mirzaei, Hamed Mirzaei. Medicinal Plants As Natural Polarizers of Macrophages: Phytochemicals and Pharmacological Effects. Current Pharmaceutical Design 2019, 25 (30) , 3225-3238. https://doi.org/10.2174/1381612825666190829154934
    47. Clare F. Megarity, David J. Timson. Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity. Bioscience Reports 2019, 39 (9) https://doi.org/10.1042/BSR20191874
    48. Christian Seca, Alessandra Ferraresi, Suratchanee Phadngam, Chiara Vidoni, Ciro Isidoro. Autophagy-dependent toxicity of amino-functionalized nanoparticles in ovarian cancer cells. Journal of Materials Chemistry B 2019, 7 (35) , 5376-5391. https://doi.org/10.1039/C9TB00935C
    49. Liisi Laaniste, Prashant K. Srivastava, Julianna Stylianou, Nelofer Syed, Silvia Cases‐Cunillera, Kirill Shkura, Qingyu Zeng, Owen J. L. Rackham, Sarah R. Langley, Andree Delahaye-Duriez, Kevin O'Neill, Matthew Williams, Albert Becker, Federico Roncaroli, Enrico Petretto, Michael R. Johnson. Integrated systems‐genetic analyses reveal a network target for delaying glioma progression. Annals of Clinical and Translational Neurology 2019, 6 (9) , 1616-1638. https://doi.org/10.1002/acn3.50850
    50. David Soussi, Jérôme Danion, Edouard Baulier, Frédéric Favreau, Ysé Sauvageon, Valentin Bossard, Xavier Matillon, Frédéric Turpin, El Mustapha Belgsir, Raphaël Thuillier, Thierry Hauet. Vectisol Formulation Enhances Solubility of Resveratrol and Brings Its Benefits to Kidney Transplantation in a Preclinical Porcine Model. International Journal of Molecular Sciences 2019, 20 (9) , 2268. https://doi.org/10.3390/ijms20092268
    51. Jean A. Boutin, Frederic Bouillaud, Elzbieta Janda, István Gacsalyi, Gérald Guillaumet, Etienne C. Hirsch, Daniel A. Kane, Françoise Nepveu, Karine Reybier, Philippe Dupuis, Marc Bertrand, Monivan Chhour, Thierry Le Diguarher, Mathias Antoine, Karen Brebner, Hervé Da Costa, Pierre Ducrot, Adeline Giganti, Vishalgiri Goswami, Hala Guedouari, Patrick P. Michel, Aakash Patel, Jérôme Paysant, Johann Stojko, Marie-Claude Viaud-Massuard, Gilles Ferry. S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization. Molecular Pharmacology 2019, 95 (3) , 269-285. https://doi.org/10.1124/mol.118.114231
    52. Veronika Jarosova, Ondrej Vesely, Petr Marsik, Jose Jaimes, Karel Smejkal, Pavel Kloucek, Jaroslav Havlik. Metabolism of Stilbenoids by Human Faecal Microbiota. Molecules 2019, 24 (6) , 1155. https://doi.org/10.3390/molecules24061155
    53. Tze-chen Hsieh, Barbara B. Doonan, Joseph M. Wu. c-Myc Metabolic Addiction in Cancers Counteracted by Resveratrol and NQO2. 2019https://doi.org/10.5772/intechopen.77852
    54. Jean A. Boutin, Gilles Ferry. Is There Sufficient Evidence that the Melatonin Binding Site MT 3 Is Quinone Reductase 2?. Journal of Pharmacology and Experimental Therapeutics 2019, 368 (1) , 59-65. https://doi.org/10.1124/jpet.118.253260
    55. Sonia Ramírez-Garza, Emily Laveriano-Santos, María Marhuenda-Muñoz, Carolina Storniolo, Anna Tresserra-Rimbau, Anna Vallverdú-Queralt, Rosa Lamuela-Raventós. Health Effects of Resveratrol: Results from Human Intervention Trials. Nutrients 2018, 10 (12) , 1892. https://doi.org/10.3390/nu10121892
    56. Uzma Saqib, Tanya T. Kelley, Siva K. Panguluri, Dongfang Liu, Rajkumar Savai, Mirza S. Baig, Stephan C. Schürer. Polypharmacology or Promiscuity? Structural Interactions of Resveratrol With Its Bandwagon of Targets. Frontiers in Pharmacology 2018, 9 https://doi.org/10.3389/fphar.2018.01201
    57. Justin Lucas, Tze-Chen Hsieh, H. Dorota Halicka, Zbigniew Darzynkiewicz, Joseph Wu. Upregulation of PD‑L1 expression by resveratrol and piceatannol in breast and colorectal cancer cells occurs via HDAC3/p300‑mediated NF‑κB signaling. International Journal of Oncology 2018, 19 https://doi.org/10.3892/ijo.2018.4512
    58. Chiara Vidoni, Eleonora Secomandi, Andrea Castiglioni, Mariarosa A.B. Melone, Ciro Isidoro. Resveratrol protects neuronal-like cells expressing mutant Huntingtin from dopamine toxicity by rescuing ATG4-mediated autophagosome formation. Neurochemistry International 2018, 117 , 174-187. https://doi.org/10.1016/j.neuint.2017.05.013
    59. Laure-Estelle Cassagnes, Monivan Chhour, Pierre Pério, Jan Sudor, Régis Gayon, Gilles Ferry, Jean A. Boutin, Françoise Nepveu, Karine Reybier. Oxidative stress and neurodegeneration: The possible contribution of quinone reductase 2. Free Radical Biology and Medicine 2018, 120 , 56-61. https://doi.org/10.1016/j.freeradbiomed.2018.03.002
    60. Uzma Saqib, Sutripta Sarkar, Kyoungho Suk, Owais Mohammad, Mirza S. Baig, Rajkumar Savai. Phytochemicals as modulators of M1-M2 macrophages in inflammation. Oncotarget 2018, 9 (25) , 17937-17950. https://doi.org/10.18632/oncotarget.24788
    61. Eamonn F. Healy, Luis Cervantes, Barret Nabona, Jacob Williams. A unified mechanism for plant polyketide biosynthesis derived from in silico modeling. Biochemical and Biophysical Research Communications 2018, 497 (4) , 1123-1128. https://doi.org/10.1016/j.bbrc.2018.02.190
    62. D. Ross, D. Siegel. Quinone Reductases. 2018, 233-250. https://doi.org/10.1016/B978-0-12-801238-3.01967-X
    63. Tze-chen Hsieh, Barbara B. Doonan, Joseph M. Wu. An Outside-In and a Reciprocal Inside-Out Hypothesis Combining Resveratrol and Its High Affinity Protein NQO2 to Target iASPP for Reinstating the Activation and Stabilization of Dysfunctional WTp53 as a Melanoma Chemopreventive Approach. 2018, 173-183. https://doi.org/10.1016/B978-0-12-813008-7.00014-X
    64. Tze-chen Hsieh, Barbara B. Doonan, Andrea Aquilato, Joseph M. Wu. Counteracting Resistance to BRAF V600E Mutation in Melanoma Using Dietary Polyphenols. 2018, 185-193. https://doi.org/10.1016/B978-0-12-813008-7.00015-1
    65. Zoe Riches, Yuejian Liu, Jacob M. Berman, Gurinder Walia, Abby C. Collier. The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2). Journal of Biochemical and Molecular Toxicology 2017, 31 (8) https://doi.org/10.1002/jbt.21921
    66. Diego Carvalho, Margot Paulino, Fabio Polticelli, Florencia Arredondo, Robert J. Williams, Juan A. Abin-Carriquiry. Structural evidence of quercetin multi-target bioactivity: A reverse virtual screening strategy. European Journal of Pharmaceutical Sciences 2017, 106 , 393-403. https://doi.org/10.1016/j.ejps.2017.06.028
    67. Sandeep K. Singh, Vishal Makadia, Shweta Sharma, Mamunur Rashid, Sudhir Shahi, Prabhat R. Mishra, Mohammed Wahajuddin, Jiaur R Gayen. Preparation and in-vitro/in-vivo characterization of trans-resveratrol nanocrystals for oral administration. Drug Delivery and Translational Research 2017, 7 (3) , 395-407. https://doi.org/10.1007/s13346-017-0362-y
    68. Alicja Sznarkowska, Anna Kostecka, Katarzyna Meller, Krzysztof Piotr Bielawski. Inhibition of cancer antioxidant defense by natural compounds. Oncotarget 2017, 8 (9) , 15996-16016. https://doi.org/10.18632/oncotarget.13723
    69. Ariane R. Guthrie, H-H. Sherry Chow, Jessica A. Martinez. Effects of resveratrol on drug- and carcinogen-metabolizing enzymes, implications for cancer prevention. Pharmacology Research & Perspectives 2017, 5 (1) , e00294. https://doi.org/10.1002/prp2.294
    70. Mikhail V. Voronin, Ilya A. Kadnikov. Contribution of Sigma‐1 receptor to cytoprotective effect of afobazole. Pharmacology Research & Perspectives 2016, 4 (6) https://doi.org/10.1002/prp2.273
    71. R.J. Aitken, L. Muscio, S. Whiting, H.S. Connaughton, B.A. Fraser, B. Nixon, N.D. Smith, G.N. De Iuliis. Analysis of the effects of polyphenols on human spermatozoa reveals unexpected impacts on mitochondrial membrane potential, oxidative stress and DNA integrity; implications for assisted reproductive technology. Biochemical Pharmacology 2016, 121 , 78-96. https://doi.org/10.1016/j.bcp.2016.09.015
    72. Lakshmi Swarna Mukhi Pidugu, J.C. Emmanuel Mbimba, Muqeet Ahmad, Edwin Pozharski, Edward A. Sausville, Ashkan Emadi, Eric A. Toth. A direct interaction between NQO1 and a chemotherapeutic dimeric naphthoquinone. BMC Structural Biology 2016, 16 (1) https://doi.org/10.1186/s12900-016-0052-x
    73. Francisco Les, Simon Deleruyelle, Laure-Estelle Cassagnes, Jean A. Boutin, Balázs Balogh, José M. Arbones-Mainar, Simon Biron, Picard Marceau, Denis Richard, Françoise Nepveu, Pascale Mauriège, Christian Carpéné. Piceatannol and resveratrol share inhibitory effects on hydrogen peroxide release, monoamine oxidase and lipogenic activities in adipose tissue, but differ in their antilipolytic properties. Chemico-Biological Interactions 2016, 258 , 115-125. https://doi.org/10.1016/j.cbi.2016.07.014
    74. Elzbieta Janda, Antonella Lascala, Concetta Martino, Salvatore Ragusa, Saverio Nucera, Ross Walker, Santo Gratteri, Vincenzo Mollace. Molecular mechanisms of lipid- and glucose-lowering activities of bergamot flavonoids. PharmaNutrition 2016, 4 , S8-S18. https://doi.org/10.1016/j.phanu.2016.05.001
    75. Tze-chen Hsieh, Sheng-Tang Wu, Dylan John Bennett, Barbara B. Doonan, Erxi Wu, Joseph M. Wu. Functional/activity network (FAN) analysis of gene-phenotype connectivity liaised by grape polyphenol resveratrol. Oncotarget 2016, 7 (25) , 38670-38680. https://doi.org/10.18632/oncotarget.9578
    76. Jean A Boutin. Quinone reductase 2 as a promising target of melatonin therapeutic actions. Expert Opinion on Therapeutic Targets 2016, 20 (3) , 303-317. https://doi.org/10.1517/14728222.2016.1091882
    77. Pengfei Fang, Min Guo. Evolutionary Limitation and Opportunities for Developing tRNA Synthetase Inhibitors with 5-Binding-Mode Classification. Life 2015, 5 (4) , 1703-1725. https://doi.org/10.3390/life5041703
    78. Ali Mobasheri, Richard Barrett‐Jolley, Caroline A. Staunton, Chris Ford, Yves Henrotin. Nutrigenomics, Inflammaging, and Osteoarthritis. 2015, 71-84. https://doi.org/10.1002/9781118930458.ch7
    79. Yangyang Chen, Ying Liu, Chen Chen, Jun Lv, Juan Zhang, Genxi Li. An electrochemical method to assay the activity of NAD(P)H: Quinone oxidoreductase 1. Sensors and Actuators B: Chemical 2015, 216 , 343-348. https://doi.org/10.1016/j.snb.2015.04.059
    80. Robert G. Britton, Christina Kovoor, Karen Brown. Direct molecular targets of resveratrol: identifying key interactions to unlock complex mechanisms. Annals of the New York Academy of Sciences 2015, 1348 (1) , 124-133. https://doi.org/10.1111/nyas.12796
    81. Stéphane Bastianetto, Caroline Ménard, Rémi Quirion. Neuroprotective action of resveratrol. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2015, 1852 (6) , 1195-1201. https://doi.org/10.1016/j.bbadis.2014.09.011
    82. Zhixiang Xu, Jing Wu, Jiyue Zheng, Haikuo Ma, Hongjian Zhang, Xuechu Zhen, Long Tai Zheng, Xiaohu Zhang. Design, synthesis and evaluation of a series of non-steroidal anti-inflammatory drug conjugates as novel neuroinflammatory inhibitors. International Immunopharmacology 2015, 25 (2) , 528-537. https://doi.org/10.1016/j.intimp.2015.02.033
    83. Mükerrem Betül Yerer, Eren Demirpolat, Ahmet Cumaoğlu, Canan Torçuk, Nefise Nalan İmamoğlu, Müberra Koşar. Comparison of natural NQO2 inhibitors as a new target for cancer treatment in different cell lines. Turkish Journal of Biochemistry 2015, 40 (3) https://doi.org/10.1515/tjb-2015-0006
    84. Keng Gat Lim, Alexander I. Gray, Nahoum G. Anthony, Simon P. Mackay, Susan Pyne, Nigel J. Pyne. Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease. Archives of Toxicology 2014, 88 (12) , 2213-2232. https://doi.org/10.1007/s00204-014-1386-4
    85. Angel L. Pey, Clare F. Megarity, David J. Timson. FAD binding overcomes defects in activity and stability displayed by cancer-associated variants of human NQO1. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2014, 1842 (11) , 2163-2173. https://doi.org/10.1016/j.bbadis.2014.08.011
    86. Lucia de Fatima Sobral Sampaio, Felipe Pantoja Mesquita, Paulo Robson Monteiro de Sousa, Jerônimo Lameira Silva, Claudio Nahum Alves. The melatonin analog 5‐MCA‐NAT increases endogenous dopamine levels by binding NRH:quinone reductase enzyme in the developing chick retina. International Journal of Developmental Neuroscience 2014, 38 (1) , 119-126. https://doi.org/10.1016/j.ijdevneu.2014.09.001
    87. Gurinder Singh, Roopa S. Pai. Recent advances of resveratrol in nanostructured based delivery systems and in the management of HIV/AIDS. Journal of Controlled Release 2014, 194 , 178-188. https://doi.org/10.1016/j.jconrel.2014.09.002
    88. Kumari Alka, J. Oliver Dolly, Barry J. Ryan, Gary T.M. Henehan. New inhibitors of the Kvβ2 subunit from mammalian Kv1 potassium channels. The International Journal of Biochemistry & Cell Biology 2014, 55 , 35-39. https://doi.org/10.1016/j.biocel.2014.07.013
    89. Rieko Nakata, Hiroyasu Inoue. Resveratrol and Cardiovascular Disease. Current Nutrition Reports 2014, 3 (3) , 163-169. https://doi.org/10.1007/s13668-014-0084-4
    90. Clare F. Megarity, Hong Keat Looi, David J. Timson. The Saccharomyces cerevisiae quinone oxidoreductase Lot6p: stability, inhibition and cooperativity. FEMS Yeast Research 2014, 14 (5) , 797-807. https://doi.org/10.1111/1567-1364.12167
    91. Tze-chen Hsieh, Chia-Yi Lin, Dylan John Bennett, Erxi Wu, Joseph M. Wu, . Biochemical and Cellular Evidence Demonstrating AKT-1 as a Binding Partner for Resveratrol Targeting Protein NQO2. PLoS ONE 2014, 9 (6) , e101070. https://doi.org/10.1371/journal.pone.0101070
    92. Clare F. Megarity, James R.E. Gill, M. Clare Caraher, Ian J. Stratford, Karen A. Nolan, David J. Timson. The two common polymorphic forms of human NRH‐quinone oxidoreductase 2 (NQO2) have different biochemical properties. FEBS Letters 2014, 588 (9) , 1666-1672. https://doi.org/10.1016/j.febslet.2014.02.063
    93. Ross Walker, Elzbieta Janda, Vincenzo Mollace. The Use of Bergamot-Derived Polyphenol Fraction in Cardiometabolic Risk Prevention and its Possible Mechanisms of Action. 2014, 1087-1105. https://doi.org/10.1016/B978-0-12-398456-2.00084-0
    94. Mark J. Acerson, Merritt B. Andrus. Selective esterification of the polyphenol resveratrol at the 4′-position. Tetrahedron Letters 2014, 55 (3) , 757-760. https://doi.org/10.1016/j.tetlet.2013.12.019
    95. Violetta Krajka-Kuźniak, Hanna Szaefer, Tomasz Stefański, Stanisław Sobiak, Michał Cichocki, Wanda Baer-Dubowska. The effect of resveratrol and its methylthio-derivatives on the Nrf2-ARE pathway in mouse epidermis and HaCaT keratinocytes. Cellular and Molecular Biology Letters 2014, 19 (3) https://doi.org/10.2478/s11658-014-0209-1
    96. Adele Chimento, Marina Sala, Isabel M. Gomez-Monterrey, Simona Musella, Alessia Bertamino, Anna Caruso, Maria Stefania Sinicropi, Rosa Sirianni, Francesco Puoci, Ortensia Ilaria Parisi, Carmela Campana, Emilia Martire, Ettore Novellino, Carmela Saturnino, Pietro Campiglia, Vincenzo Pezzi. Biological activity of 3-chloro-azetidin-2-one derivatives having interesting antiproliferative activity on human breast cancer cell lines. Bioorganic & Medicinal Chemistry Letters 2013, 23 (23) , 6401-6405. https://doi.org/10.1016/j.bmcl.2013.09.054
    97. John M Pezzuto, Tamara P Kondratyuk, Talysa Ogas. Resveratrol derivatives: a patent review (2009 – 2012). Expert Opinion on Therapeutic Patents 2013, 23 (12) , 1529-1546. https://doi.org/10.1517/13543776.2013.834888
    98. Sarah E. St. John, Katherine C. Jensen, SooSung Kang, Yafang Chen, Barbara Calamini, Andrew D. Mesecar, Mark A. Lipton. Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2. Bioorganic & Medicinal Chemistry 2013, 21 (19) , 6022-6037. https://doi.org/10.1016/j.bmc.2013.07.037
    99. Talysa Ogas, Tamara P. Kondratyuk, John M. Pezzuto. Resveratrol analogs: promising chemopreventive agents. Annals of the New York Academy of Sciences 2013, 1290 (1) , 21-29. https://doi.org/10.1111/nyas.12196
    100. Kevin K.K. Leung, Brian H. Shilton. Chloroquine Binding Reveals Flavin Redox Switch Function of Quinone Reductase 2. Journal of Biological Chemistry 2013, 288 (16) , 11242-11251. https://doi.org/10.1074/jbc.M113.457002
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