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). ...

The functions of quinone reductase 2 have eluded researchers for decades even though a genetic polymorphism is associated with various neurological disorders. Employing enzymatic studies using adrenochrome as a substrate, we show that quinone reductase 2 is specific for the reduction of adrenochrome, whereas quinone reductase 1 shows no activity. We also solved the crystal structure of quinone reductase 2 in complexes with dopamine and adrenochrome, two compounds that are structurally related to catecholamine quinones. Detailed structural analyses delineate the mechanism of quinone reductase 2 specificity toward catechol quinones in comparison with quinone reductase 1; a side-chain rotational difference between quinone reductase 1 and quinone reductase 2 of a single residue, phenylalanine 106, determines the specificity of enzymatic activities. These results infer functional differences between two homologous enzymes and indicate that quinone reductase 2 could play important roles in the regulation of catecholamine oxidation processes that may be involved in the etiology of Parkinson disease.Cytosolic quinone reductases consist of two enzymes termed quinone reductase 1 (also referred to as QR1, 2 NQO1, DTdiaphorase) and quinone reductase 2 (also referred to as QR2, NQO2) which catalyze the two-electron reduction of quinones without the formation of reactive intermediates (1). They play important roles against oxidative stress imposed by quinones. Quinone reductase 2 was first described in 1961 (2), although its biological function has eluded scientists for decades until recently (3-5). However, quinone reductase 1 has been very well studied (6). In particular, conclusive evidence points to QR1 having a protective function for cells against the toxicity of electrophiles and reactive forms of oxygen. In addition, its induction protects cells against carcinogenesis. Therefore, QR1 is acknowledged as belonging to the group of enzymes classified as phase 2 detoxification enzymes.There are two major classes of quinones: 1,4-quinones (paraquinones or p-quinones, see Fig. 1) and 1,2-quinones (orthoquinones, catechol quinones or o-quinones). Both classes of quinones can be derived from oxidation of xenobiotics as well as endogenous molecules. 1,4-Quinones include vitamin K analogues, such as VK3 (menadione), whereas catechol quinones include the oxidation products of catecholamines, amino acid tyrosine as well as estradiols (7,8).Although QR2 and QR1 have high sequence and structural similarities, they possess significantly different catalytic actions (9). Both QR1 and QR2 can catalyze the two-electron reduction of p-quinones such as menadione (vitamin K3), only QR1 uses NADH and NADPH as electron donors. Instead, QR2 can use N-ribosyldihydronicotinamide (NRH) or a variety of NRH analogues as electron donors in the reduction of quinones in vitro (see Fig. 1) (10). While NADH and NADPH are electron donors for a variety of enzymes in various reactions and their biological metabolism and concentrations are very well charact...

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