Trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites.
Trypanosomatids are protozoan organisms that cause serious diseases, including African sleeping sickness, Chagas' disease, and leishmaniasis, affecting about 30 million people in the world. These parasites contain the unusual dithiol trypanothione [T(SH)(2)] instead of glutathione (GSH) as the main intracellular reductant, and they have replaced the otherwise ubiquitous GSH/glutathione reductase redox couple with a T(SH)(2)/trypanothione reductase (TR) system. The reason for the existence of T(SH)(2) in parasitic organisms has remained an enigma. Here, we show that T(SH)(2) is able to intercept nitric oxide and labile iron and form a dinitrosyl-iron complex with at least 600 times higher affinity than GSH. Accumulation of the paramagnetic dinitrosyl-trypanothionyl iron complex in vivo was observed in Trypanosoma brucei and Leishmania infantum exposed to nitric oxide. While the analogous dinitrosyl-diglutathionyl iron complex formed in mammalian cells is a potent irreversible inhibitor of glutathione reductase (IC(50)=4 microM), the T(SH)(2) complex does not inactivate TR even at millimolar levels. The peculiar capacity of T(SH)(2) to sequester NO and iron in a harmless stable complex could explain the predominance of this thiol in parasites regularly exposed to NO.-Bocedi, A., Dawood, K. F., Fabrini, R., Federici, G., Gradoni, L., Pedersen, J. Z., Ricci, G. Trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites.
Bocedi
Alessio
A
Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, via della Ricerca Scientifica 1, 00133 Rome, Italy.
Dawood
Kutayba F
KF
Fabrini
Raffaele
R
Federici
Giorgio
G
Gradoni
Luigi
L
Pedersen
Jens Z
JZ
Ricci
Giorgio
G
D000818:Animals; D014355:Chagas Disease / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D018314:Leishmania infantum / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000378:metabolism
D009589:Nitrogen Oxides; D015800:Protozoan Proteins; D009569:Nitric Oxide; C073661:dinitrosyl iron complex; C044809:trypanothione; D007501:Iron; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D013095:Spermidine