Review Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism R. Luise Krauth-Siegel ⁎, Marcelo A. Comini Biochemie-Zentrum der Universität Heidelberg, 69120 Heidelberg, Germany article info abstract Article history: Received 25 January 2008 Received in revised form 26 February 2008 Accepted 11 March 2008 Available online 18 March 2008 Trypanosomes and leishmania, the causative agents of several tropical diseases, possess a unique redox metabolism which is based on trypanothione. The bis(glutathionyl)spermidine is the central thiol that delivers electrons for the synthesis of DNA precursors, the detoxification of hydroperoxides and other trypanothione-dependent pathways. Many of the reactions are mediated by tryparedoxin, a distant member of the thioredoxin protein family. Trypanothione is kept reduced by the parasite-specific flavoenzyme trypanothione reductase. Since glutathione reductases and thioredoxin reductases are missing, the reaction catalyzed by trypanothione reductase represents the only connection between the NADPH- and the thiol- based redox metabolisms. Thus, cellular thiol redox homeostasis is maintained by the biosynthesis and reduction of trypanothione. Nearly all proteins of the parasite-specific trypanothione metabolism have proved to be essential. © 2008 Elsevier B.V. All rights reserved. Keywords: Trypanothione Trypanosoma Thiol metabolism Thioredoxin Glutaredoxin Tryparedoxin Peroxiredoxin Glutathionylation Glutathione peroxidase 1. Introduction Trypanosomatids are protozoan organisms of the order Kineto- plastida that parasitize a wide variety of invertebrate and vertebrate hosts. The most relevant specimens for human and animal health belong to two genera: Trypanosoma and Leishmania, which account for over half a million annual human deaths in (sub)tropical regions around the world. In sub-Saharan countries T. brucei rhodesiense and T. b. gambiense are the causative agents of African sleeping sickness and Nagana cattle disease is caused by T. b. brucei, T. vivax and T. congolense. In the New World, T. cruzi is responsible of Chagas' disease. Different Leishmania species occur world-wide and cause inter alia black fever, espundia, oriental sore and Kala-Azar. Crithidia fasciculata is an apathogenic trypanosomatid that serves as a useful model organism. Trypanosomatids represent one of the earliest branches of eukaryotic evolution with mitochondria and microbodies [1]. The parasites show a large number of biochemical, morphological and genetic peculiarities with the thiol redox metabolism being one of the unique pathways. The genome sequencing projects of T. brucei [2], T. cruzi [3] and L. major [4] have revealed that trypanosomatids lack genes for glutathione reductase (GR) and thioredoxin reductase (TrxR) as well as catalase and selenocysteine-containing glutathione peroxidases. While in most eukaryotic organisms the glutathione (GSH)/GR and thioredoxin (Trx)/ TrxR systems maintain the intracellular thiol redox homeostasis, trypanosomatids possess a redox metabolism that is based on the low molecular mass dithiol trypanothione [bis(glutathionyl) spermi- dine; T(SH) 2 ] [5] and trypanothione reductase (TR) — which keeps it in the reduced form (Table 1) [for reviews see [23,24]]. T(SH) 2 and/or TR have also been described in the flagellated green algae Euglena gracilis [19] and the amitochondriate pathogenic amoebae Entamoeba histo- lytica [20] and Naegleria fowleri [22]. Interestingly, E. gracilis and N. fowleri were reported to contain both GR as well as TR [19,22]. The absence of the trypanothione system in mammals, the lack of a functional redundancy within the parasite thiol system together with the sensitivity of trypanosomes against oxidative stress render the components of this metabolism attractive drug target molecules [for recent reviews see 24 and 25]. The thorough analysis of the trypanothione metabolism and its control mechanisms will certainly reveal additional unprecedented features and putative new targets for a selective antiparasitic drug development. 2. Thiol redox homeostasis in trypanosomes In any living organism, the cellular redox homeostasis is affected by an excess of reactive oxygen (ROS) and nitrogen species originating as by-product of aerobic growth or from the environment. Redox- active thiol groups in proteins and low molecular mass compounds play key roles as redox buffers that balance any disturbance of the intracellular redox state [26,27]. Depending on the level and extension of the oxidative stress, the cells may establish short- or long-term Biochimica et Biophysica Acta 1780 (2008) 1236–1248 ⁎ Corresponding author. Tel.: +49 6221 54 41 87; fax: +49 6221 54 5586. E-mail addresses: luise.krauth-siegel@bzh.uni-heidelberg.de (R.L. Krauth-Siegel), marcelo.comini@bzh.uni-heidelberg.de (M.A. Comini). 0304-4165/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2008.03.006 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen