Trypanothione: A unique bis-glutathionyl derivative in trypanosomatids |
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Authors: | Bruno Manta,Marcelo Comini,Andrea Medeiros,Martí n Hugo,Madia Trujillo,Rafael Radi |
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Affiliation: | 1. Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay. Mataojo 2020, Montevideo 11400, Uruguay;2. Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. Avenida General Flores 2125, Montevideo 11800, Uruguay;3. Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo, Uruguay. Avenida General Flores 2125, Montevideo 11800, Uruguay |
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Abstract: | BackgroundTrypanosomatids 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 reviewThis 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 conclusionsBased 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 significanceThe 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. |
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Keywords: | 1-C-Grx, monothiol glutaredoxin 2-C-Grx, dithiol glutaredoxin CBS, cystathionine-β-synthase CGL, cystathionine-γ-lyase CHAP, cysteine histidine-dependent amidohydrolases/peptidases (protein domain) CS, cysteine synthase DMPO, 5,5&prime -dimethyl-l-pyrroline-N-oxide DNIC, dinitrosyl iron complex DNTIC, dinitrosyl-trypanothione iron complex eEF1B, eukaryotic elongation factor 1B EPR, electron paramagnetic resonance Fe&ndash S, iron&ndash sulfur cluster on a protein GPx, glutathione peroxidase Grx, glutaredoxin GSH, reduced glutathione GshA, γ-glutamyl-cysteine synthetase GshB, glutathione synthetase GSNO, nitrosoglutathione Gsp, mono-glutathionylspermidine GspS, mono-glutathionyl spermidine synthetase GSSG, glutathione disulfide GST, glutathione-S-transferase HED, hydroxyethyl disulfide ISC, iron sulfur cluster in general, related to the biosynthetic machinery LIP, &ldquo labile&rdquo or chelatable iron pool LMW, low molecular weight MSR, methionine sulfoxide reductase MST, 3-mercaptopyruvate sulfurtransferase ODC, ornithine decarboxylase Prx, peroxiredoxin Pxs, peroxidases (general term) PxIII, glutathione-type tryparedoxin-dependent peroxidase III RnR, ribonucleotide reductase RTS, reverse transsulfuration SAT, serine acetyltransferase Spd, spermidine SpS, spermidine synthase T(SH)2, dihydrotrypanothione TDR1, thiol-dependent reductase 1 Trx, thioredoxin TrxR, thioredoxin reductase TryR, trypanothione reductase TryS, trypanothione synthetase TS2, trypanothione disulfide TXN, tryparedoxin UMSBP, universal minicircle sequence binding protein |
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