Characterization of the melatoninergic MT3 binding site on the NRH:quinone oxidoreductase 2 enzyme

Mailliet, François; Ferry, Gilles; Vella, F; Berger, Sylvie; Cogé, Francis; Chomarat, Pascale; Mallet, Catherine; Guenin, Sophie-Pénélope; Guillaumet, Gérald; Viaud‐Massuard, Marie‐Claude; Yous, Saı̈d; Delagrange, Philippe; Boutin, Jean A.

doi:10.1016/j.bcp.2005.09.030

Cited by 114 publications

(105 citation statements)

References 44 publications

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“…The enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1, QR1) and the NRH:quinone oxidoreductase 2 (NQO2, QR2), which is identical with the melatonin binding site MT3 (71,72), have been previously detected in normal and immortalized melanocytes and keratinocytes as well as in adult dermal fibroblasts (18). In the present study we extended this investigation to melanoma cell lines.…”

Section: Discussionmentioning

confidence: 69%

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

Fischer

Żmijewski²,

Zbytek³

et al. 2006

Int J Oncol

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Abstract.Melatonin has been shown to have oncostatic effects on malignant melanoma in vitro and in vivo. We studied the growth suppressive effects of melatonin over a wide range of concentrations in four melanoma cell lines (SBCE2, WM-98, WM-164 and SKMEL-188) representative for different growth stages and phenotype. Melanoma cells were incubated with melatonin 10 -12 -10 -3 M, and proliferation and clonogenicity was assessed at 12 h and 14 days, respectively. We also determined the expression of cytosolic quinone oxidoreductases NQO1, NQO2 (known as MT3 receptor) and nuclear receptor ROR· by RT-PCR. Melatonin at pharmacological concentrations (10 -3 -10 -7 M) suppressed proliferation in all melanoma cell lines. In SKMEL-188 cells cultured in serum-free media, melatonin at low concentrations (10 -12 -10 -10 M) also slightly attenuated the proliferation. The effects of pharmacological doses of melatonin were confirmed in the clonogenic assay. Expression of NQO1 was detected in all cell lines, whereas NQO2 and nuclear receptor ROR· including its isoform ROR·4 were present only in SBCE2, WM-164 and WM-98. Thus, melatonin differentially suppressed proliferation in melanoma cell lines of different behaviour. The intensity of the oncostatic response to melatonin could be related to the cell-line specific pattern of melatonin cellular receptors and cytosolic binding protein expression.

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Section: Discussionmentioning

confidence: 69%

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

Fischer

Żmijewski²,

Zbytek³

et al. 2006

Int J Oncol

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“…This study showed strong melatonin binding in the QR2 active site containing FAD in the oxidised state [11] . Nevertheless, the K d values for melatonin in binding assays were lower than the IC 50 values obtained for melatonin via in vitro and cellular assays [14] . These results are the foundation upon which melatonin has been considered a candidate for an endogenous cosubstrate [25] .…”

Section: Research Highlightmentioning

confidence: 59%

“…The same discrepancy between binding and activity in QR2 assays was observed when the QR2-selective melatonin analogue 5-MCA-NAT was investigated as an inhibitor [14,26,27] . However, the 5-MCA-NAT has only one orientation in QR2 active site, which is different of that exhibited by classical QR2 inhibitors as in human [22] as in chicken [27] .…”

Section: Research Highlightmentioning

confidence: 83%

“…The capability to accept a myriad of quinones and small compounds as substrates turn QR2 into a multifunctional enzyme. In mammals, QR2 is present in different tissues [1,14] that contain different endogenous compounds. Additionally, each tissue is susceptible to be targeted by exogenous compounds with the ability to function as substrates for QR2 catalysis.…”

Section: Introductionmentioning

confidence: 99%

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NRH: Quinone Reductase activity results in the accumulation of endogenous dopamine in the retina

et al. 2015

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Dopamine quinone is substrate of the NRH: Quinone Reductase enzyme (QR2) in the retina. The capability of accumulates endogenous dopamine in a neural tissue explains the association of certain neuropsychiatric diseases with polymorphisms in the QR2 promoter that causes overexpression via loss of the capability to bind repressors. However, QR2 doubly reduce other small compounds present in neural and non-neural tissues, being its physiology tissue dependent. In this context, the function of the neurohormone melatonin and analogues in the active site of this multifunctional enzyme is discussed in this mini review. The flavoenzyme Ribosyldihydronicotinamide dehydrogenase (quinone), EC 1.10.99.2 (NRH: Quinone Reductase, QR2) is an unpredicted member of the quinone reductase family of phase II detoxifying enzymes [1] because its detoxifying activity produces reactive quinones and free radicals [2] . In addition, the natural QR2 cosubstrates are NRH (N-ribosyl-dihydronicotinamide) and NMH (N-methyl-dihydronicotinamide) [3][4][5] . This enzyme is inhibited by quercetin, resveratrol, benzo[a]pyrene [3][4][5] , some protein kinases inhibitors [6,7] , antimalarial drugs [8] and many others synthetized analogues compounds [9,10] . QR2 is able to doubly reduce quinones such as menadione, a synthetic vitamin K precursor, the coenzymes Q0-10 Keywords[11] and anti-cancer pro-drugs such as CB1954 [12] . The kinetics of this 24-kDa cytosolic flavoprotein proceeds via a double displacement mechanism [13] . Through this mechanism, FAD is reduced by the cosubstrate, which then diffuses out from the binding pocket, permitting occupation of the active site by the substrate. In this type of catalysis, the excess substrate competes with the cosubstrate, or vice-versa, resulting in the inhibition of the enzyme. Therefore, the effect of small compounds in QR2 catalysis is concentration dependent. The capability to accept a myriad of quinones and small compounds as substrates turn QR2 into a multifunctional enzyme. In mammals, QR2 is present in different tissues [1,14] that contain different endogenous compounds. Additionally, each tissue is susceptible to be targeted by exogenous compounds with the ability to function as substrates for QR2 catalysis. Therefore, QR2 physiology appears to be tissue-dependent. Dopamine plays a role in light-adapting events in retinal physiology [15] , whereas in the brain, attention, memory and other cognitive processes are regulated by dopamine [16] . A great achievement in the investigation of QR2 physiology was the finding that ortho-quinones such as dopa-quinone RESEARCH HIGHLIGHT

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“…Thus, a third melatonin binding site, MT3, was recently identified as the enzyme NRH:quinone oxydoreductase 2 (QR2) [8]. Another protein, GPR50 (also termed H9 and ML1X), is an orphan GPCR that is about 45% identical overall to human MT1 and MT2.…”

Section: Introductionmentioning

confidence: 99%

The pattern of melatonin receptor expression in the brain may influence antidepressant treatment

et al. 2007

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SummaryThe pineal hormone melatonin produces most of its biological effects via G protein-coupled receptors MT1 and MT2. In mammals, these receptors are expressed in various tissues and organs including in the brain. Recent research points to a putative role of MT1/MT2 dimerization as a mechanism that could determine the receptor-mediated biological effects of melatonin. Brain content and the ratios between MT1 and MT2 receptors are affected by illness, e.g., Alzheimer's disease, and by prolonged drug treatment, e.g., antidepressants. New drugs with antidepressant properties that bind and activate melatonin receptors have been discovered. We hypothesize that endogenous, i.e., low, levels of melatonin could contribute to antidepressant effects depending on the expression pattern of melatonin receptors in the brain. Hence, we propose that a prolonged treatment with classical antidepressant drugs alters the brain ratio of MT1/MT2 receptors to enable the endogenous melatonin, which is secreted during the night, to further improve the antidepressant effects. A corollary of this hypothesis is that antidepressants would be less effective in conditions of pathologically altered brain melatonin receptors, e.g., in Alzheimer's patients or due to genetic polymorphisms. If our hypothesis is confirmed, supplementing classical antidepressant treatment with an appropriate dose of a melatonin receptor agonist might be used to improve antidepressant effects in subjects with a susceptible pattern of brain melatonin receptor expression.

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Characterization of the melatoninergic MT3 binding site on the NRH:quinone oxidoreductase 2 enzyme

Cited by 114 publications

References 44 publications

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

NRH: Quinone Reductase activity results in the accumulation of endogenous dopamine in the retina

The pattern of melatonin receptor expression in the brain may influence antidepressant treatment

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