Chemical and enzyme-mediated oxidation of the serotonergic neurotoxin 5,7-dihydroxytryptamine: mechanistic insights.
The oxidation chemistry and biochemistry of the serotonergic neurotoxin 5,7-dihydroxytryptamine (1) has been studied under anaerobic and aerobic conditions in aqueous solution at physiological pH. Under anaerobic conditions, one-electron oxidants (ferricytochrome c, peroxidase/H2O2, ceruloplasmin, Cu2+) generate a radical intermediate. Dimerization of the C(6)-centered resonance form of this radical followed by secondary oxidations yields 3-(2-aminoethyl)-6-[3-(2-aminoethyl)-1,7-dihydro- 5-hydroxy-7-oxo-6H-indol-6-ylidene]-1-H-indole-5,7(4H,6H)-dione. Under aerobic conditions, molecular O2 attacks the C(4)-centered 1 radical to yield a hydroperoxy radical which decomposes to 5-hydroxytryptamine-4,7-dione (2). Autoxidation of 1 proceeds by primary attack by molecular O2 on a C(4)-centered carbanion to form a superoxide-radical complex. This rearranges to a C(4)-centered hydroperoxide which decomposes to 2. A C(6)-centered carbanion of 1 combines with 2 to give, ultimately, 6,6'-bi-5-hydroxytryptamine-4,7-dione (3). Trace concentrations of transition metal ions (Fe3+, Fe2+, Cu2+, Mn2+) catalyze the autoxidation of 1 by catalytic cycles in which a hydroperoxide intermediate plays key roles. A byproduct of the transition metal-catalyzed oxidation of 1 is superoxide, O2-. Because of its enormous basicity O2- facilitates deprotonation of 1. The C(4)-centered carbanion so produced is oxidized by molecular O2 or by the hydroperoxy radical (HO2) to give radical intermediates and thence 2 and 3. Mechanistic pathways leading to the various products of oxidation of 1 are proposed and the potential roles of oxidation reactions of the indolamine are related to its neurodegenerative properties.
Tabatabaie
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Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019.
Dryhurst
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D015116:5,7-Dihydroxytryptamine / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D002374:Catalase / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D008670:Metals / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D010101:Oxygen Consumption; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D003574:Cytochrome c Group; D006878:Hydroxides; D008670:Metals; D013481:Superoxides; D015116:5,7-Dihydroxytryptamine; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D002374:Catalase; D009195:Peroxidase; D014442:Monophenol Monooxygenase; D013482:Superoxide Dismutase; D002570:Ceruloplasmin; D010100:Oxygen