Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinones and quinoid compounds to hydroquinones. Although the role of a homologue, NAD(P)H:quinone oxidoreductase 1 (NQO1), is well defined in oxidative stress, neoplasia, and carcinogenesis, little is known about the mechanism of actions of NQO2 in these cellular responses. Whether NQO2 has any role in tumor necrosis factor (TNF) signaling was investigated using keratinocytes derived from wild-type and NQO2 knockout (NQO2-/-) mice. Although exposure of wild-type cells to TNF led to activation of nuclear factor-kappaB (NF-kappaB) and IkappaBalpha kinase, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation, this cytokine had no effect on NQO2-/- cells. Deletion of NQO2 also abolished TNF-induced c-Jun NH2-terminal kinase, Akt, p38, and p44/p42 mitogen-activated protein kinase activation. The induction of various antiapoptotic gene products (MMP-9, cyclin D1, COX-2, IAP1, IAP2, Bcl-2, cFLIP, and XIAP) by TNF was also abolished in NQO2-/- cells. This correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, Annexin V staining, and caspase activation. In agreement with this, we also found that TNF activated NQO2, and NQO2-specific small interfering RNA abrogated the TNF-induced NQO2 activity and NF-kappaB activation. Overall, our results indicate that deletion of NQO2 plays a differential role in TNF signaling pathway: by suppressing cell survival signals and potentiating TNF-induced apoptosis.
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PMID:Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases. 1794 34

Melatonin exerts its biological effects through at least two transmembrane G-protein-coupled receptors, MT1 and MT2, and a lower-affinity cytosolic binding site, designated MT3. MT3 has recently been identified as QR2 (quinone reductase 2) (EC 1.10.99.2) which is of significance since it links the antioxidant effects of melatonin to a mechanism of action. Initially, QR2 was believed to function analogously to QR1 in protecting cells from highly reactive quinones. However, recent studies indicate that QR2 may actually transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. Therefore it is hypothesized that inhibition of QR2 in certain cases may lead to protection of cells against these highly reactive species. Since melatonin is known to inhibit QR2 activity, but its binding site and mode of inhibition are not known, we determined the mechanism of inhibition of QR2 by melatonin and a series of melatonin and 5-hydroxytryptamine (serotonin) analogues, and we determined the X-ray structures of melatonin and 2-iodomelatonin in complex with QR2 to between 1.5 and 1.8 A (1 A=0.1 nm) resolution. Finally, the thermodynamic binding constants for melatonin and 2-iodomelatonin were determined by ITC (isothermal titration calorimetry). The kinetic results indicate that melatonin is a competitive inhibitor against N-methyldihydronicotinamide (K(i)=7.2 microM) and uncompetitive against menadione (K(i)=92 microM), and the X-ray structures shows that melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site. These results provide new insights into the binding mechanisms of melatonin and analogues to QR2.
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PMID:Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2. 1825 26

Vitamin K1, K2, and K3 are essential nutrients associated with blood clotting and bone metabolism. Quinone oxidoreductases [NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2)] are among the selected enzymes that catalyze reduction of vitamin K to vitamin K hydroquinone. NQO1 catalyzes high affinity reduction of vitamin K3 but has only weak affinity for reduction of vitamin K1 and K2. Vitamin K hydroquinone serves as a cofactor for vitamin K gamma-carboxylase that catalyzes gamma-carboxylation of specific glutamic acid residues in Gla-factors/proteins leading to their activation and participation in blood clotting and bone metabolism. Concomitant with Gla modification, a reduced vitamin K molecule is converted to vitamin K epoxide, which is converted back to vitamin K by the enzyme vitamin K epoxide reductase to complete vitamin K cycle. Vitamin K is also redox cycled. One-electron reduction of vitamin K3 leads to the formation of semiquinone that in the presence of oxygen is oxidized back to vitamin K3. Oxygen is reduced to generate reactive oxygen species (ROS) that causes oxidative stress and cytotoxicity. Vitamin K is used as radiation sensitizer or in mixtures with other chemotherapeutic drugs to treat several types of cancer. ROS generated in redox cycling contributes to anticancer activity of vitamin K. NQO1 competes with enzymes that redox cycle vitamin K and catalyzes two-electron reduction of vitamin K3 to hydroquinone. This skips formation of semiquinone and ROS. Therefore, NQO1 metabolically detoxifies vitamin K3 and protects cells against oxidative stress and other adverse effects. On the contrary, NQO2 catalyzes metabolic activation of vitamin K3 leading to cytotoxicity. The role of NQO1 and NQO2 in metabolic detoxification and/or activation of vitamin K1 and K2 remains to be determined. Future studies are also required to identify the enzymes that catalyze high affinity reduction of vitamin K1 and K2 to hydroquinone for use in gamma-carboxylation reactions.
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PMID:Quinone oxidoreductases and vitamin K metabolism. 1837 91

NAD(P)H dehydrogenase quinone 2 (NQO2) is a quinone reductase whose functions include the reduction of both oxidative stress during the redox cycle and neurotoxicity caused by the metabolism of catecholamines. We have investigated a functional non-synonymous exon 3 single nucleotide polymorphism (rs1143684) within the NQO2 gene for association with cognitive decline using a cohort of 722 community-dwelling older individuals aged 50 years and over. The volunteers had completed tests that measured fluid intelligence, processing speed, immediate/delayed verbal recall and semantic memory. We observed a nominal significant association between this polymorphism and the trajectory of delayed memory recall over time (p=0.029). No other associations were seen with the decline of other cognitive abilities.
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PMID:Investigation of a functional quinine oxidoreductase (NQO2) polymorphism and cognitive decline. 1853 95

1. Resveratrol, a polyphenol in red wine, has a cardioprotective effect. Resveratrol-targeting protein (RTP) has been purified using a resveratrol affinity column (RAC) and has been identified as quinone reductase type 2 (NQO2). We hypothesize that NQO2 is the target protein of resveratrol in vascular smooth muscle cells (VSMC) and that resveratrol inhibits proliferation of VSMC through its action on NQO2. In the present study, we investigated the correlation between NQO2 regulation and cell proliferation in VSMC in response to resveratrol treatment. 2. The RTP was purified using RAC and was detected with a NQO2 polyclonal antibody. The VSMC were incubated with resveratrol (1, 10 and 50 micromol/L) for 24, 48 and 72 h. Cell proliferation was detected by cell counting and bromodeoxyuridine (BrdU) assay. A lentiviral vector incorporating NQO2 short interference (si) RNA of short hairpin design was constructed and transduced into VSMC. Real-time quantitative polymerase chain reaction was used to measure NQO2 mRNA levels; NQO2 expression was determined by western blot analysis. 3. Using RAC, we extracted a 26 kDa protein from aortic smooth muscle, which was referred to as RTP-26. Proliferation of VSMC was inhibited by resveratrol in a concentration- and time-dependent manner. The mRNA and protein expression of NQO2 was also repressed by resveratrol in a concentration- and time-dependent manner. A similar pattern of inhibition was observed for cells treated with resveratrol (25 micromol/L) as for cells transduced with a lentiviral vector containing siRNA sequences against NQO2. 4. Collectively, these data indicate that the suppression of VSMC proliferation mediated by resveratrol correlates with NQO2 downregulation.
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PMID:Negative regulation of quinone reductase 2 by resveratrol in cultured vascular smooth muscle cells. 1867 25

2,5-Diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is a novel antitumor diaziridinyl benzoquinone derivative designed to be bioactivated by the two-electron reductase NAD(P)H:quinone oxidoreductase (NQO1) and is currently in clinical trials. NQO1 is expressed at high levels in many solid tumors. RH1 cytotoxicity has been shown previously to be NQO1-dependent. The purpose of this study was to investigate whether other reducing enzymes such as cytochrome b(5) reductase (b5R), cytochrome P450 reductase (P450R), dihydronicotinamide riboside:quinone oxidoreductase 2 (NQO2), and xanthine oxidase/xanthine dehydrogenase (XO/XDH) also contribute to the bioactivation and cytotoxicity of RH1 in human tumor cells. For these studies, we established a series of stable MDA468 breast cancer cell lines overexpressing various levels of NQO1, b5R, P450R, and NQO2 and compared RH1-induced growth inhibition [3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium and sulforhodamine B analysis] and interstrand DNA cross-linking (comet analysis) in both parental MDA468 cells and transfected clones. RH1 toxicity correlated with NQO1 and NQO2 but not with either b5R or P450R activity levels in the respective series of transfected MDA468 cell clones. Enzymatic assays showed that RH1 was an in vitro substrate for xanthine oxidase. However, XO/XDH protein and activity could not be detected in a variety of human tumor cell lines. These studies suggest that NQO1 and NQO2 are the principal enzymatic determinants of RH1 bioactivation in MDA468 tumor cells and that b5R, P450R, and XDH/XO are unlikely to play major roles. Our studies also suggest that NQO2 may be particularly relevant as a bioactivation system for RH1 in NQO1-deficient tumors such as leukemias and lymphomas.
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PMID:Dissecting the role of multiple reductases in bioactivation and cytotoxicity of the antitumor agent 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1). 1879 27

The physiological function of NAD(P)H:quinone oxidoreductase (NQO1, DT-diaphorase) is to detoxify potentially reactive quinones by direct transfer of two electrons. A similar detoxification role has not been established for its homologue NRH:quinone oxidoreductase 2 (NQO2). Estrogen quinones, including estradiol(E(2))-3,4-Q, generated by estrogen metabolism, are thought to be responsible for estrogen-initiated carcinogenesis. In this investigation, we have shown for the first time that NQO2 catalyzes the reduction of electrophilic estrogen quinones and thereby may act as a detoxification enzyme. ESI and MALDI mass spectrometric binding studies involving E(2)-3,4-Q with NQO2 clearly support the formation of an enzyme-substrate physical complex. The problem of spontaneous reduction of substrate by cofactor, benzyldihydronicotinamide riboside (BNAH), was successfully overcome by taking advantage of the ping-pong mechanism of NQO2 catalysis. The involvement of the enzyme in the reduction of E(2)-3,4-Q was further supported by addition of the inhibitor quercetin to the assay mixture. NQO2 is a newly discovered binding site (MT3) of melatonin. However, addition of melatonin to the assay mixture did not affect the catalytic activity of NQO2. Preliminary kinetic studies show that NQO2 is faster in reducing estrogen quinones than its homologue NQO1. Both UV and liquid chromatography-tandem mass spectrometry assays unequivocally corroborate the reduction of estrogen ortho-quinones by NQO2, indicating that it could be a novel target for prevention of breast cancer initiation.
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PMID:Evidence for NQO2-mediated reduction of the carcinogenic estrogen ortho-quinones. 1899 84

Phase II enzymes are induced primarily through the common electrophile response element (EpRE) signaling. Studies performed in different cell types and with different inducer appear to indicate variation in the upstream signaling pathways involved in the induction of these phase II genes. Nonetheless, whether variation in signaling among phase II genes in the same cell with the same inducer is unclear. This study is designed to answer this question using human bronchial epithelial cells (HBE1 cells) as a model and screening with a variety of protein kinase inhibitors with varying degrees of specificity. Two electrophiles, 4-hydroxynonenal (HNE) and acrolein, induced the expression of phase II genes (GCLC, GCLM, NQO1, NQO2, HO-1, and GSTM-1). Nrf2 silencing significantly decreased the induction of all of these genes, confirming the involvement of Nrf2-EpRE signaling. ERK and p38MAPK inhibitors had no effect, while a JNK inhibitor abrogated the GCLC and GCLM induction by HNE, but not that by acrolein. Among the PKC inhibitors used, one eliminated gene induction by HNE and acrolein, while two others showed no effects. One PI3K inhibitor decreased the induction of GCLM, NQO1, NQO2 and HO-1, but not GCLC and GST-M1; on the other hand, the inhibitory effects of another PI3K inhibitor on gene induction seems to be gene- and inducer- specific. In conclusion, our data suggest that although phase II genes are coordinately induced through Nrf2-EpRE signaling by electrophiles, the upstream signaling pathways involved are gene- and inducer- specific. It is also suggested that commercial kinase inhibitors may produce non-specific effects on phase II gene expression via mechanisms unrelated to their purported specificity.
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PMID:Signaling pathways involved in phase II gene induction by alpha, beta-unsaturated aldehydes. 1965 97

A range of triazoloacridin-6-ones functionalized at C5 and C8 have been synthesized and evaluated for ability to inhibit NQO1 and NQO2. The compounds were computationally docked into the active site of NQO1 and NQO2, and calculated binding affinities were compared with IC(50) values for enzyme inhibition. Excellent correlation coefficients were demonstrated suggesting a predictive QSAR model for this series of structurally similar analogues. From this we have identified some of these triazoloacridin-6-ones to be the most potent NQO2 inhibitors so far reported.
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PMID:Triazoloacridin-6-ones as novel inhibitors of the quinone oxidoreductases NQO1 and NQO2. 2003 59

The cytosolic quinone oxidoreductases NQO1 and NQO2 protect cells against oxidative stress by detoxifying quinones and preventing redox cycling. In this study, we used double knockout (DKO) mice deficient for NQO1 and NQO2 to investigate the role of these antioxidative enzymes in a two-stage model of inflammatory skin carcinogenesis. In this model, tumors are caused by exposure to topical carcinogen dimethylbenz(a)anthracene or benzo(a)pyrene (BP) followed by twice weekly application of proinflammatory phorbol 12-myristate 13-acetate. On this classic chemical carcinogenesis protocol, DKO mice showed a significantly higher skin tumor frequency and multiplicity compared with control wild-type or single knockout mice. Analysis of skin from wild-type and DKO mice exposed to BP for 6, 12, or 24 hours revealed a relative delay in the activation of p53, p63, p19ARF, and apoptosis in DKO mice, consistent with a negative modifier role for NQO1/NQO2 in carcinogenesis. Our findings offer genetic evidence of the significance of quinone oxidoreductases NQO1 and NQO2 in limiting chemical skin carcinogenesis.
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PMID:Inactivation of the quinone oxidoreductases NQO1 and NQO2 strongly elevates the incidence and multiplicity of chemically induced skin tumors. 3038 11


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