Trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites

Abstract

Trypanosomatids are protozoan organ isms 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 re dox 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 mamma lian cells is a potent irreversible inhibitor of glutathione reductase (IC50 4 M), 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 predomi nance 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. Trypano thione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites