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

Abstract

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.

The Dithiol Glutaredoxins of African Trypanosomes Have Distinct Roles and Are Closely Linked to the Unique Trypanothione Metabolism

“…Although the nature of this protein-free iron-containing chromophore is not yet known, the ability of T(SH) 2 to act as a strong chelating agent probably plays a major role. As reported recently, T(SH) 2 can intercept nitric oxide and labile iron to form a stable free dinitrosyl-trypanothione-iron complex (58). All reconstitution mixtures of Grx1 had diminished activity in the HED assay in accordance with an active site Cys participating in ligand binding.…”

Leishmania antimony resistance: what we know what we can learn from the field

“…Resistance to NO involves trypanothione metabolism, which is also crucial for antimony resistance (Bocedi et al 2010). Experimental evidence supports the notion that NO may be a crucial factor that can modify the antimony response of Leishmania populations.…”

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

“…NO inactivates cruzain by S-nitrosylation of the binding site (12), but T. cruzi uses trypanothione reductase to convert NO into a harmless species (13). Therefore, it has been hypothesized that NO donor drugs may be useful against T. cruzi infection by producing exogenous NO (14).…”