title: Trypanothione: a unique bis-glutathionyl derivative in trypanosomatids.
abstract: 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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Institut Pasteur de Montevideo, Montevideo, Uruguay. bmanta@pasteur.edu.uy
authors: Bruno
authors: B
authors: Manta
authors: Marcelo
authors: M
authors: Comini
authors: Andrea
authors: A
authors: Medeiros
authors: Martín
authors: M
authors: Hugo
authors: Madia
authors: M
authors: Trujillo
authors: Rafael
authors: R
authors: Radi
mesh_terms: D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014351:Trypanosomatina / Q000378:metabolism*
chemical_list: D016877:Oxidants; D013438:Sulfhydryl Compounds; C044809:trypanothione; D005978:Glutathione; D013095:Spermidine