Influence of L-Cysteine on the Oxidation Chemistry of Serotonin

L-Cysteine (CySH) intervenes in the normal electrochemically driven oxidation of 5-hydroxytryptamine (5-HT; serotonin) at physiological pH by scavenging the quinone imine proximate oxidation product of this indolic neurotransmitter to give 4-S-cysteinyl-5-hydroxy-tryptamine (4-S-CyS-5-HT). The latter cysteinyl conjugate is more easily electro-oxidized than 5-HT and, in the presence of free CySH, undergoes a complex series of reactions leading to 8-(2-aminoethyl)-1,2,3,5,6,9-hexahydro-5,9-dioxo-pyrrolo [3, 2-g] [1, 4] benzothiazine-2-carboxylic acid (20) and N-[7-[(2-amino-2-carboxyethyl) thio]-3-(2-aminoethyl)-1,4-dihydro-4-oxo-5H-indol-5-ylidene]-L-cysteine (4). CySH also reacts with another normal oxidation product of 5-HT, tryptamine-4,5-dione, to give 4 and 20. There is evidence that aberrant oxidative metabolism of 5-HT occurs in the brains of Alzheimer′s Disease patients. In the event that such reactions occur in the cytoplasm of serotonergic nerve terminals or axons they would necessarily expose electrophilic intermediates and products to the intraneuronal nucleophiles CySH and GSH. The results of this study indicate that 4 and 20 might represent aberrant oxidative metabolites formed in such reactions. However, the ease of oxidation of 4-S-CyS-5-HT compared to 5-HT suggest that this conjugate is likely to be only a transient species in vivo under conditions where the neurotransmitter is oxidized.