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Trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites
Author(s) -
Bocedi Alessio,
Dawood Kutayba F.,
Fabrini Raffaele,
Federici Giorgio,
Gradoni Luigi,
Pedersen Jens Z.,
Ricci Giorgio
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-146407
Subject(s) - nitric oxide , glutathione , biochemistry , chemistry , leishmania , leishmania infantum , glutathione reductase , reductase , biology , enzyme , leishmaniasis , visceral leishmaniasis , parasite hosting , glutathione peroxidase , immunology , organic chemistry , world wide web , computer science
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 |xM), 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. FASEB J. 24, 1035‐1042 (2010). www.fasebj.org