Studies of the melatonin binding site location onto quinone reductase 2 by directed mutagenesis

Boutin, Jean A.; Saunier, Carine; Guenin, Sophie-Pénélope; Berger, Sylvie; Moulharat, Natacha; Gohier, Arnaud; Delagrange, Philippe; Cogé, Francis; Ferry, Gilles

doi:10.1016/j.abb.2008.04.040

Cited by 18 publications

(12 citation statements)

References 39 publications

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“…We cannot exclude that these are distinct phenomena and that the generation of hydroquinones or related metabolites that naturally accompany NQO2 activity has little to do with autophagy modulation. The question of whether active or rather activable (ligand-free) NQO2 suppress autophagy could be addressed by site-specific mutagenesis of NQO2 and generation of enzyme-dead and constitutively active mutants, but so far, this objective has failed, as none of the mutants we tested was totally inactive or insensitive to ligands [ 47 ]. In addition, the activity of NQO2 is difficult to establish in living cells, because it depends not only on the levels of quinones but also on the availability of its co-substrates such as nicotinamide mononucleotide (NMN) or related compounds [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

et al. 2021

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Dietary flavonoids stimulate autophagy and prevent liver dysfunction, but the upstream signaling pathways triggered by these compounds are not well understood. Certain polyphenols bind directly to NRH-quinone oxidoreductase 2 (NQO2) and inhibit its activity. NQO2 is highly expressed in the liver, where it participates in quinone metabolism, but recent evidence indicates that it may also play a role in the regulation of oxidative stress and autophagy. Here, we addressed a potential role of NQO2 in autophagy induction by flavonoids. The pro-autophagic activity of seven flavonoid aglycons correlated perfectly with their ability to inhibit NQO2 activity, and flavones such as apigenin and luteolin showed the strongest activity in all assays. The silencing of NQO2 strongly reduced flavone-induced autophagic flux, although it increased basal LC3-II levels in HepG2 cells. Both flavones induced AMP kinase (AMPK) activation, while its reduction by AMPK beta (PRKAB1) silencing inhibited flavone-induced autophagy. Interestingly, the depletion of NQO2 levels by siRNA increased the basal AMPK phosphorylation but abrogated its further increase by apigenin. Thus, NQO2 contributes to the negative regulation of AMPK activity and autophagy, while its targeting by flavones releases pro-autophagic signals. These findings imply that NQO2 works as a flavone receptor mediating autophagy and may contribute to other hepatic effects of flavonoids.

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Section: Discussionmentioning

confidence: 99%

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

et al. 2021

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“…QR2 does not recognise or use NAD(P)H, as opposed to QR1. The physiological role of MT 3 site has not yet been identified, but it is suspected that modulation of the activity of this enzyme can affect the cellular redox status (Boutin et al, ). Therefore, it could be expected that this binding site of melatonin mediates the effects of the hormone on the cellular redox status, including the activity of antioxidant enzymes.…”

Section: Discussionmentioning

confidence: 99%

Role of melatonin receptor MT₂ and quinone reductase II in the regulation of the redox status of 3T3‐L1 preadipocytes in vitro

Adamczyk-Sowa

Sowa

Żwirska-Korczala

et al. 2013

Cell Biology International

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We have examined the role of melatonin receptor MT2 and quinone reductase II in the regulation of the redox status of preadipocytes (3T3-L1) in vitro. 3T3-L1 cells were treated with melatonin at a physiological concentration (10(-9) mol/L) and a supraphysiological (pharmacological) concentration (10(-3) mol/L) for 24 h. Luzindole (10(-4) mol/L), an antagonist of MT2 receptor, and prazosin (10(-5) mol/L), an inhibitor of quinone reductase II, were added 30 min before subsequent exposure of the cells to melatonin. The level of oxidative stress was determined by the analysis of activities of enzymes neutralising reactive oxygen species, and determination of the malondialdehyde (MDA) content. Melatonin increased activities of manganese and copper-zinc superoxide dismutase (MnSOD, Cu/ZnSOD) and catalase (CAT) at both a physiological concentration (10(-9) mol/L) and a pharmacological concentration (10(-3) mol/L). MDA content was unchanged, whereas activities of glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-Rd) were increased only by the physiological concentration. Both effects were partially inhibited by luzindole, but not prazosin. These observations suggest that melatonin, acting at least partially via MT2 receptors, can increase antioxidant enzymes activities in 3T3-L1 preadipocytes.

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“…In animals, melatonin also binds directly to the catalytic site of quinone reductase 2 (QR2, E.C. 1.10.99.2), a cytosolic molecule, to modulate the activity of this enzyme; that modulation may be either up or down regulation (119, 120). Importantly, the change in QR2 activity may further play a key role in ROS generation or detoxification (121).…”

Section: Functional Evolution Of Melatoninmentioning

confidence: 99%

Melatonin Synthesis and Function: Evolutionary History in Animals and Plants

et al. 2019

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Melatonin is an ancient molecule that can be traced back to the origin of life. Melatonin's initial function was likely that as a free radical scavenger. Melatonin presumably evolved in bacteria; it has been measured in both α-proteobacteria and in photosynthetic cyanobacteria. In early evolution, bacteria were phagocytosed by primitive eukaryotes for their nutrient value. According to the endosymbiotic theory, the ingested bacteria eventually developed a symbiotic association with their host eukaryotes. The ingested α-proteobacteria evolved into mitochondria while cyanobacteria became chloroplasts and both organelles retained their ability to produce melatonin. Since these organelles have persisted to the present day, all species that ever existed or currently exist may have or may continue to synthesize melatonin in their mitochondria (animals and plants) and chloroplasts (plants) where it functions as an antioxidant. Melatonin's other functions, including its multiple receptors, developed later in evolution. In present day animals, via receptor-mediated means, melatonin functions in the regulation of sleep, modulation of circadian rhythms, enhancement of immunity, as a multifunctional oncostatic agent, etc., while retaining its ability to reduce oxidative stress by processes that are, in part, receptor-independent. In plants, melatonin continues to function in reducing oxidative stress as well as in promoting seed germination and growth, improving stress resistance, stimulating the immune system and modulating circadian rhythms; a single melatonin receptor has been identified in land plants where it controls stomatal closure on leaves. The melatonin synthetic pathway varies somewhat between plants and animals. The amino acid, tryptophan, is the necessary precursor of melatonin in all taxa. In animals, tryptophan is initially hydroxylated to 5-hydroxytryptophan which is then decarboxylated with the formation of serotonin. Serotonin is either acetylated to N -acetylserotonin or it is methylated to form 5-methoxytryptamine; these products are either methylated or acetylated, respectively, to produce melatonin. In plants, tryptophan is first decarboxylated to tryptamine which is then hydroxylated to form serotonin.

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Studies of the melatonin binding site location onto quinone reductase 2 by directed mutagenesis

Cited by 18 publications

References 39 publications

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Role of melatonin receptor MT₂ and quinone reductase II in the regulation of the redox status of 3T3‐L1 preadipocytes in vitro

Melatonin Synthesis and Function: Evolutionary History in Animals and Plants

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Studies of the melatonin binding site location onto quinone reductase 2 by directed mutagenesis

Cited by 18 publications

References 39 publications

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

Role of melatonin receptor MT2 and quinone reductase II in the regulation of the redox status of 3T3‐L1 preadipocytes in vitro

Melatonin Synthesis and Function: Evolutionary History in Animals and Plants

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Role of melatonin receptor MT₂ and quinone reductase II in the regulation of the redox status of 3T3‐L1 preadipocytes in vitro