Trypanothione: a unique bis-glutathionyl derivative in trypanosomatids.

Bruno Manta (1) , Marcelo Comini (1) , Andrea Medeiros (1, 2) , Martín Hugo (2, 3) , Madia Trujillo (2, 3) , Rafael Radi (2, 3)

1 Institut Pasteur de Montevideo
2 Departamento de Bioquímica, Facultad de Medicina
3 Center for Free Radical and Biomedical Research

BACKGROUND: Trypanosomatids are early-diverging eukaryotes devoid of the major disulfide reductases - glutathione reductase and thioredoxin reductase - that control thiol-redox homeostasis in most organisms. These protozoans have evolved a unique thiol-redox system centered on trypanothione, a bis-glutathionyl conjugate of spermidine. Notably, the trypanothione system is capable to sustain several cellular functions mediated by thiol-dependent (redox) processes. SCOPE OF REVIEW: This review provides a summary of some historical and evolutionary aspects related to the discovery and appearance of trypanothione in trypanosomatids. It also addresses trypanothione's biosynthesis, physicochemical properties and reactivity towards biologically-relevant oxidants as well as its participation as a cofactor for metal binding. In addition, the role of the second most abundant thiol of trypanosomatids, glutathione, is revisited in light of the putative glutathione-dependent activities identified in these organisms. MAJOR CONCLUSIONS: Based on biochemical and genome data, the occurrence of a thiol-redox system that is strictly dependent on trypanothione appears to be a feature unique to the order Kinetoplastida. The properties of trypanothione, a dithiol, are the basis for its unique reactivity towards a wide diversity of oxidized and/or electrophilic moieties in proteins and low molecular weight compounds from endogenous or exogenous sources. Novel functions have emerged for trypanothione as a potential cofactor in iron metabolism. GENERAL SIGNIFICANCE: The minimalist thiol-redox system, developed by trypanosomatids, is an example of metabolic fitness driven by the remarkable physicochemical properties of a glutathione derivative. From a pharmacological point of view, such specialization is the Achilles' heel of these ancient and deadly parasites. This article is part of a Special Issue entitled Cellular functions of glutathione.

Domains: Life Sciences [q-bio]

Bruno Manta, Marcelo Comini, Andrea Medeiros, Martín Hugo, Madia Trujillo, et al.. Trypanothione: a unique bis-glutathionyl derivative in trypanosomatids.. BBA - Biochimica et Biophysica Acta, 2013, 1830 (5), pp.3199-216. ⟨10.1016/j.bbagen.2013.01.013⟩. ⟨pasteur-00847176⟩