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 (QR(2)), rather than a membrane melatonin receptor. Based on the data available and our preliminary studies, we hypothesize that melatonin is a co-substrate of QR(2). 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 FADH(2) while melatonin is converted to N-1-acetyl-N-2-formyl-5-methoxykynuramine and/or cyclic 3-hydroxymelatonin. QR(2) 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 QR(2).