Old and new inhibitors of quinone reductase 2

Ferry, Gilles; Hecht, Sabrina; Berger, Sylvie; Moulharat, Natacha; Cogé, Francis; Guillaumet, Gérald; Leclerc, Véronique; Yous, Saı̈d; Delagrange, Philippe; Boutin, Jean A.

doi:10.1016/j.cbi.2010.04.006

Cited by 49 publications

(46 citation statements)

References 41 publications

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“…This observation matches our other recently reported observations that stronger inhibitors tend to adopt only one orientation in the hQR2 active site 26. Furthermore, two other aspects of those comparisons should be pointed out: 1) Ferry et al 27. addressed several of these questions by testing various inhibitors (including MLT, S29434 and S26695) using a set of conditions, particularly regarding substrates, co‐substrates, their nature and concentrations; and 2) Initial observations on MCA‐NAT/MT3 relationships were mainly conducted in binding assays, by displacement of 2‐iodo‐MLT.…”

Section: Discussionsupporting

confidence: 91%

X‐ray structural studies of quinone reductase 2 nanomolar range inhibitors

et al. 2011

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Quinone reductase 2 (QR2) is one of two members comprising the mammalian quinone reductase family of enzymes responsible for performing FAD mediated reductions of quinone substrates. In contrast to quinone reductase 1 (QR1) which uses NAD(P)H as its co-substrate, QR2 utilizes a rare group of hydride donors, N-methyl or N-ribosyl nicotinamide. Several studies have linked QR2 to the generation of quinone free radicals, several neuronal degenerative diseases, and cancer. QR2 has been also identified as the third melatonin receptor (MT3) through in cellulo and in vitro inhibition of QR2 by traditional MT3 ligands, and through recent X-ray structures of human QR2 (hQR2) in complex with melatonin and 2-iodomelatonin. Several MT3 specific ligands have been developed that exhibit both potent in cellulo inhibition of hQR2 nanomolar, affinity for MT3. The potency of these ligands suggest their use as molecular probes for hQR2. However, no definitive correlation between traditionally obtained MT3 ligand affinity and hQR2 inhibition exists limiting our understanding of how these ligands are accommodated in the hQR2 active site. To obtain a clearer relationship between the structures of developed MT3 ligands and their inhibitory properties, in cellulo and in vitro IC 50 values were determined for a representative set of MT3 ligands (MCA-NAT, 2-I-MCANAT, prazosin, S26695, S32797, and S29434). Furthermore, X-ray structures for each of these ligands in complex with hQR2 were determined allowing for a structural evaluation of the binding modes of these ligands in relation to the potency of MT3 ligands.

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Section: Discussionsupporting

confidence: 91%

X‐ray structural studies of quinone reductase 2 nanomolar range inhibitors

et al. 2011

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“…Thus, besides the antioxidant cascade [87], there seems also to be chelating cascade as well. Obviously, reducing˙OH formation via the [176,177] chelating actions of melatonin and its metabolic kin would limit the molecular havoc that leads to accumulated oxidative damage and physiological inefficiency.…”

Section: Oxidizing Agent Referencesmentioning

confidence: 99%

Melatonin: an ancient molecule that makes oxygen metabolically tolerable

Manchester

Coto‐Montes

Boga

et al. 2015

Journal of Pineal Research

808

650

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Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, antiinflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatoninsynthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress.

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“…Nosjean and his co-workers reported that “MT3” is equivalent to NQO2 (Nosjean et al, 2000). The three modulators for the “MT3” receptor, ranked from the lowest to highest affinity, are melatonin, resveratrol, and compound S29434 (Ferry et al, 2010). …”

Section: Melatonin Receptorsmentioning

confidence: 99%

Melatonin membrane receptors in peripheral tissues: Distribution and functions

Slominski

Reíter

Schlabritz‐Loutsevitch

et al. 2012

Molecular and Cellular Endocrinology

583

470

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Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes.

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Old and new inhibitors of quinone reductase 2

Cited by 49 publications

References 41 publications

X‐ray structural studies of quinone reductase 2 nanomolar range inhibitors

X‐ray structural studies of quinone reductase 2 nanomolar range inhibitors

Melatonin: an ancient molecule that makes oxygen metabolically tolerable

Melatonin membrane receptors in peripheral tissues: Distribution and functions

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