Melatonin as a naturally occurring co-substrate of quinone reductase-2, the putative MT₃ melatonin membrane receptor: Hypothesis and significance

The nature of the MT₃ melatonin receptor/binding site has been a long pondered mystery for scientists. Even though it is a presumptive membrane receptor, neither its transduction cascade nor its biological consequences, after its stimulation, have been uncovered. Moreover, solid data support the idea that the MT₃ melatonin binding site is an enzyme, quinone reductase 2 (QR₂), rather than a membrane melatonin receptor. Based on the data available and our preliminary studies, we hypothesize that melatonin is a co-substrate of QR₂. We surmise that melatonin binds to a co-substrate binding site (MT₃ binding site) donating an electron to the enzyme co-factor, flavin adenine dinucleotide (FAD). FAD can be reduced to either FADH or FADH₂ while melatonin is converted to N ¹-acetyl-N²-formyl-5-methoxykynuramine and/or cyclic 3-hydroxymelatonin. QR₂ is considered to be a detoxifying and antioxidant enzyme and its behavior changes depending on available co-substrates. As a naturally occurring substance, melatonin's levels fluctuate with the light/dark cycle, with aging and with health/disease state. As a result, these alterations in melatonin production under physiological or pathological conditions would probably influence the activity of QR₂.