Old and new inhibitors of quinone reductase 2.
Quinone reductase 2 is a cytosolic enzyme which catalyses the reduction of quinones, such as menadione and coenzymes Q. Despite a relatively close sequence-based resemblance to NAD(P)H:quinone oxidoreductase 1 (QR1), it has many different features. QR2 is the third melatonin binding site (MT3). It is inhibited in the micromolar range by melatonin, and does not accept conventional phosphorylated nicotinamides as hydride donors. QR2 has a powerful capacity to activate quinones leading to unexpected toxicity situations. In the present paper, we report the characterization of three QR2 modulators: melatonin, resveratrol and S29434. The latter compound inhibits QR2 activity with an IC(50) in the low nanomolar range. The potency of the modulators ranged as follows, from the least to the most potent: melatonin<resveratrol<S29434. These molecular tools might permit to explore and better understand the relationship existing between QR2 catalytic activity and the various pathological situations in which QR2 has a key role.
Ferry
Gilles
G
Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy sur Seine, France.
Hecht
Sabrina
S
Berger
Sylvie
S
Moulharat
Natacha
N
Coge
Francis
F
Guillaumet
Gérald
G
Leclerc
Véronique
V
Yous
Saïd
S
Delagrange
Philippe
P
Boutin
Jean A
JA
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008550:Melatonin / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011763:Pyrrolizidine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D044094:Receptors, Melatonin / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D018411:Spodoptera; D013267:Stilbenes / Q000494:pharmacology; D013379:Substrate Specificity
D017931:DNA Primers; D004791:Enzyme Inhibitors; D005663:Furans; C550454:N-(2-(2-methoxy-6H-dipyrido(2,3-a-3,2-e)pyrrolizin-11-yl)ethyl)-2-furamide; D011725:Pyridines; D011763:Pyrrolizidine Alkaloids; D044094:Receptors, Melatonin; D011994:Recombinant Proteins; D013267:Stilbenes; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D008550:Melatonin; D000077185:Resveratrol