Reactions of the putative neurotoxin tryptamine-4,5-dione with L-cysteine and other thiols.
Tryptamine-4,5-dione (1) is formed by oxidation of 5-hydroxytryptamine by reactive oxygen and reactive nitrogen species. Dione 1 is a powerful electrophile that can covalently modify cysteinyl residues of proteins and deactivate key enzymes. Thus, 1 has been suggested to play a role in the degeneration of serotonergic neurons in brain disorders such as Alzheimer's disease or evoked by amphetamine drugs. However, if formed in the brain, it is also likely that 1 would react with low molecular weight thiols such as cysteine (CySH) and glutathione (GSH). The resulting metabolites might not only contribute to the degeneration of serotonergic neurons but also, perhaps, serve as biomarkers of such neurodegeneration. In this investigation, it is shown that in oxygenated buffer at pH 7.4 dione 1 reacts with CySH and other low molecular weight sulfhydryls such as GSH, N-acetylcysteine, and cysteamine to form, first, the corresponding 7-S-thioethers of the dione. However, unlike the glutathionyl and N-acetylcysteinyl conjugates of 1, the 7-S-cysteinyl conjugate is very unstable at pH 7.4 forming a number of novel products, the nature of which are dependent on the relative concentrations of 1 and CySH. These products have been isolated, and spectroscopic and other evidence is provided in support of their proposed chemical structures.
Jiang
Xiang-Rong
XR
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
Wrona
Monika Z
MZ
Alguindigue
Susan S
SS
Dryhurst
Glenn
G
D003545:Cysteine / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry; D045563:Indolequinones / Q000737:chemistry* / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D009420:Nervous System / Q000187:drug effects; D014363:Tryptamines / Q000737:chemistry* / Q000633:toxicity
D045563:Indolequinones; D014363:Tryptamines; C060213:tryptamine-4,5-dione; D005978:Glutathione; D003545:Cysteine