Bis(glutathionyl)spermine and Other Novel Trypanothione Analogues in Trypanosoma cruzi

摘要: Trypanosomatids differ from other cells in their ability to conjugate glutathione with the polyamine spermidine form antioxidant metabolite trypanothione (N 1,N 8-bis(glutathionyl)spermidine). In Trypanosoma cruzi, is synthesized by an unusual synthetase/amidase (TcTryS) that forms both glutathionylspermidine and trypanothione. Because T. cruzi unable synthesize putrescine dependent on uptake of exogenous polyamines high affinity transporters, synthesis may be circumstantially limited lack spermidine. Here, we show parasite able circumvent potential shortage conjugating physiological substrates sources (spermine, N 8-acetylspermidine, N-acetylspermine). Novel thiols were purified epimastigotes, structures determined matrix-assisted laser desorption ionization time-of-flight analysis 12-bis(glutathionyl)spermine, 1-glutathionyl-N 12-acetylspermine, respectively. Structures confirmed enzymatic recombinant TcTryS, which catalyzes formation these compounds kinetic parameters equivalent or better than those Despite containing similar amounts spermine spermidine, trypomastigotes, amastigotes preferentially Bis(glutathionyl)spermine disulfide a substrate reductase, comparable homotrypanothione disulfides. The broad specificity TcTryS could exploited design polyamine-based inhibitors metabolism.