[Melatonin binding site MT3 is QR2: state of the art]

Melatonin is a neurohormone primarily synthesized in the pineal gland at night. It has numerous functions in various pathophysiological situations, including anti-oxidant properties at pharmacological concentrations (1 microM and above). It is believed that melatonin acts through three main targets: two 7TM receptors (MT1 and MT2) and one atypical binding site called MT3. This last binding site has been purified in our laboratory and is designated as quinone reductase 2 (QR2, E.C. 1.10.99.2). This enzyme has several individualistic features. It does not recognize standard nicotinamide derivatives as co-substrates, but rather, it recognizes rare ones such as N-ribosylnicotinamide. Among other features of this enzyme, two are of major importance: 1) experiments from Dr Jaiswal (Houston, Texas) laboratory with QR2-/- mice and with cells derived from them demonstrated that this enzyme is implicated in the toxicological activation of menadione, and thus, may have an activation rather than a detoxification role, as formerly believed, and 2) the polyphenol resveratrol, a molecule with anti-oxidant properties, is a potent inhibitor of QR2 ( approximately 30 nM). This talk will briefly summarize these findings, and will present our working hypotheses, molecular tools and findings on several aspects of the possible relationship between QR2 and melatonin, in particular those suggesting a mechanism for the anti-oxidant activity of melatonin.