Catalytic Properties of NAD(P)H:Quinone Oxidoreductase-2 (NQO2), a Dihydronicotinamide Riboside Dependent Oxidoreductase

Wu, Kaijin; Knox, Richard J.; Sun, Xiaoyan; Joseph, Pius; Jaiswal, Anil K.; Zhang, Di; Deng, P. S. K.; Chen, Shiuan

doi:10.1006/abbi.1997.0344

Cited by 133 publications

(128 citation statements)

References 24 publications

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“…We have tested a number of related compounds, including quercetin and baicalein. Quercetin is shown to be a strong inhibitor of QR2 enzymatic activity, with similar affinity toward QR2 as resveratrol, consistent with an earlier report (30), whereas baicalein, a strong QR1 enzymatic activity inhibitor (49), does not inhibit QR2 activity significantly. Also, flavone itself does not inhibit QR2 enzymatic activity.…”

Section: Qr2 Could Be the Common Target Of The Chemopreventive Polyphsupporting

confidence: 90%

Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol^,

et al. 2004

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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, upregulates the expression of cellular antioxidant enzymes and cellular resistance to oxidative stress.Resveratrol (trans-3,4′,5-trihydroxystilbene) is a phyto-polyphenol that occurs in grapes and a variety of medicinal plants. Because of its abundance in grapes, it is present in significant amount in grape products such as grape juice and wines, particularly red wine (1). The revealing of resveratrol as a cancer chemopreventive agent in 1997 (2) sparked extensive research on its chemopreventive properties (3). Resveratrol has been tested on a variety of cancers in animal model studies. As in the case of the 1997 study, Jang et al. (2) demonstrated in a mouse model that resveratrol is effective in prevention of DMBA-(dimethylbenzanthracene) and TPA-(tetradecanoylphorbol-13-acetate) induced skin cancer. Application of 1, 5, 10, or 25 µM of resveratrol with TPA twice a week for 18 weeks reduced the number of skin tumors per mouse by 68, 81, 76, or 98%, respectively, and the percentage of mice with tumors was lowered by 50, 63. 63, or 88%. In mouse models of colon cancer and small intestinal cancer, resveratrol prevents cancer formation with 100 and 70% efficacy, respectively (4, 5). † This work was supported in part by National Institute of Health Grant R21 CA104424. ‡ The atomic coordinates and structure factors (PDB code 1SG0) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptResveratrol has been suggested to block the multistep process of carcinogenesis, namely, tumor initiation, promotion, and progression (3). Despite extensive investigation, no clear molecular basis for the actions of resveratrol has emerged. A variety of hypotheses have been proposed to explain its functions: antioxidant effects, proapoptotic effects, cell-cycle regulation, inhibition of protein kinases, regulation of NFκB and Iκ3, and modulation of estrogen effects (3, 6). ...

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Section: Qr2 Could Be the Common Target Of The Chemopreventive Polyphsupporting

confidence: 90%

Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol^,

et al. 2004

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“…This observation is contrary to the perceived lack of enzymatic function of NQO2, but is not inconsistent with the literature. Nicotinamide adenine dinucleotide is used to elute hrNQO2 during affinity chromatography with cibacron blue as a ligand and hrNQO2 has a K m for NADH threeto four-fold higher than that of NQO1 (Wu et al, 1997). The 43 carboxy terminal residues of NQO1 which interact with the ADP section of NADH do not totally restore NADH binding or activity to NQO2 (Wu et al, 1997) and additional amino-acid differences in NQO2 compared with NQO1 in the catalytic site are believed to contribute to the difference in affinity.…”

Section: Discussionmentioning

confidence: 99%

“…hrNQO1, hrNQO2 (prepared as described in Wu et al (1997)), bovine serum albumin (BSA), lactose, Tris-HCL, MMC, phosphate dibasic, phosphate monobasic, deduced NADH, dicoumarol, quercetin and ammonium formate were purchased from Sigma-Aldrich (Poole, Dorset, UK). Phosphate-buffered saline (PBS) was purchased from Invitrogen (Paisley, UK) HPLC grade acetonitrile and methanol were purchased from Fischer Scientific (Loughborough, UK).…”

Section: Methodsmentioning

confidence: 99%

Reduction of mitomycin C is catalysed by human recombinant NRH:quinone oxidoreductase 2 using reduced nicotinamide adenine dinucleotide as an electron donating co-factor

Jamieson

Tung

Knox³

et al. 2006

Br J Cancer

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NRH:Quinone Oxidoreductase 2 (NQO2) has been described as having no enzymatic activity with nicotinamide adenine dinucleotide (NADH) or NADPH as electron donating cosubstrates. Mitomycin C (MMC) is both a substrate for and a mechanistic inhibitor of the NQO2 homologue NQO1. NRH:quinone oxidoreductase 2 catalysed the reduction of MMC at pH 5.8 with NADH as a co-factor. This reaction results in species that inhibit the NQO2-mediated metabolism of CB1954. In addition, MMC caused an increase in DNA cross-links in a cell line transfected to overexpress NQO2 to an extent comparable to that observed with an isogenic NQO1-expressing cell line. These data indicate that NQO2 may contribute to the metabolism of MMC to cytotoxic species.

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“…As an alternative approach to the use of CB1954, it has recently been shown that there is potent endogenous CB1954-reducing activity in human tumour cells (Wu et al, 1997), although reduction is only detected in the presence of the cosubstrate dihydronicotinamide riboside (NRH). The latent activity is due to an endogenous enzyme designated NAD(P)H quinone oxidoreductase 2 (NQO2) (Wu et al, 1997), which can be considered as a human NRH-dependent nitroreductase (Knox et al, 2000a).…”

Section: XVmentioning

confidence: 99%

“…The latent activity is due to an endogenous enzyme designated NAD(P)H quinone oxidoreductase 2 (NQO2) (Wu et al, 1997), which can be considered as a human NRH-dependent nitroreductase (Knox et al, 2000a). A simple reduced pyridinium derivative designated EP-0152R can, like NRH, act as cosubstrate for NQO2, and CB1954 is an effective antitumour agent when given with EP-0152R in vivo against experimental human tumour xenografts (Knox et al, 2000b).…”

Section: XVmentioning

confidence: 99%

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

et al. 2003

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Catalytic Properties of NAD(P)H:Quinone Oxidoreductase-2 (NQO2), a Dihydronicotinamide Riboside Dependent Oxidoreductase

Cited by 133 publications

References 24 publications

Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol^,

Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol^,

Reduction of mitomycin C is catalysed by human recombinant NRH:quinone oxidoreductase 2 using reduced nicotinamide adenine dinucleotide as an electron donating co-factor

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

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Catalytic Properties of NAD(P)H:Quinone Oxidoreductase-2 (NQO2), a Dihydronicotinamide Riboside Dependent Oxidoreductase

Cited by 133 publications

References 24 publications

Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol,

Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol,

Reduction of mitomycin C is catalysed by human recombinant NRH:quinone oxidoreductase 2 using reduced nicotinamide adenine dinucleotide as an electron donating co-factor

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

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Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol^,

Crystal Structure of Quinone Reductase 2 in Complex with Resveratrol^,