First insights into regiospecific transnitrosation reactions between tryptophan derivatives: melatonin as an...

Melatonin, a derivative of the essential amino acid tryptophan, has been portrayed as a hormone, a tissue factor, an autocoid, a paracoid, and a vitamin with antioxidative capabilities. In the present study a novel reaction which cannot be attributed to any of these suggested features, i.e. the transfer of the nitroso-function from N-nitrosotryptophan derivatives to melatonin, is unequivocally demonstrated. In the lipophilic buffer dimethylsulfoxide reaction of N-acetyl-N-nitrosotryptophan (NANT) with melatonin was very slow (k = 1.5 x 10(-6)/m/s), but reversible as shown by 15N-NMR spectrometry. These measurements demonstrated also that the thermodynamical equilibrium lies on the side of N-nitrosomelatonin (NOMela). Quantum-chemical calculations performed with the third-generation density functional B97-2 additionally predicted that this is also the case in an aqueous environment. In fact, reaction of melatonin with either NANT or N-nitrosotryptophan located at the endothelin-1 fragment 16-21 yielded NOMela with a rate constant of 1.7 +/- 0.5/m/s as shown by capillary zone electrophoresis. Interestingly, the known reactive nitrogen oxide species scavenger, piperazine, did not inhibit the NANT-dependent nitrosation of melatonin, thus very strongly indicating a direct transnitrosation reaction. All of these capabilities are known from the reaction of S-nitrosothiols with thiolate anions and are believed to be highly important in the transport and targeting of nitric oxide.