Platyhelminth mitochondrial and cytosolic redox homeostasis is controlled by a single thioredoxin glutathione reductase and dependent on selenium and glutathione

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Título

Platyhelminth mitochondrial and cytosolic redox homeostasis is controlled by a single thioredoxin glutathione reductase and dependent on selenium and glutathione

Tema

SELENIO
GLUTATIONA REDUCTASA
2008
BIBLIOGRAFIA NACIONAL QUIMICA

Abstract

Platyhelminth parasites are a major health problem in developing countries. In contrast to their mammalian hosts, platyhelminth thiol-disulfide redox homeostasis relies on linked thioredoxin-glutathione systems, which are fully dependent on thioredoxin-glutathione reductase (TGR), a promising drug target. TGR is a homodimeric enzyme comprising a glutaredoxin domain and thioredoxin reductase (TR) domains with a C-terminal redox center containing selenocysteine (Sec). In this study, we demonstrate the existence of functional linked thioredoxin-glutathione systems in the cytosolic and mitochondrial compartments of Echinococcus granulosus, the platyhelminth responsible for hydatid disease. The glutathione reductase (GR) activity of TGR exhibited hysteretic behavior regulated by the [GSSG]/[GSH] ratio. This behavior was associated with glutathionylation by GSSG and abolished by deglutathionylation. The Km and kcat values for mitochondrial and cytosolic thioredoxins (9.5 μM and 131 s–1, 34 μM and 197 s–1, respectively) were higher than those reported for mammalian TRs. Analysis of TGR mutants revealed that the glutaredoxin domain is required for the GR activity but did not affect the TR activity. In contrast, both GR and TR activities were dependent on the Sec-containing redox center. The activity loss caused by the Sec-to-Cys mutation could be partially compensated by a Cys-to-Sec mutation of the neighboring residue, indicating that Sec can support catalysis at this alternative position. Consistent with the essential role of TGR in redox control, 2.5 μM auranofin, a known TGR inhibitor, killed larval worms in vitro. These studies establish the selenium- and glutathione-dependent regulation of cytosolic and mitochondrial redox homeostasis through a single TGR enzyme in platyhelminths

Autor

Bonilla, Mariana
Denicola, Ana
Novoselov, S. V.
Turanov, A. A.
Protasio, A.
Izmendi, Darwin
Gladyshev, V. N.

Fuente

Journal of Biological Chemistry v. 283, no. 26, 2008. -- p. 17898-17907

Editor

American Society for Biochemistry and Molecular Biology

Fecha

2008

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PDF

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Tipo

Artículo

Identificador

DOI 10.1074/jbc.M710609200

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PDF
Fecha de agregación
June 6, 2014
Colección
Bibliografía Nacional Química
Tipo de Elemento
Document
Etiquetas
,
Citación
Bonilla, Mariana, “Platyhelminth mitochondrial and cytosolic redox homeostasis is controlled by a single thioredoxin glutathione reductase and dependent on selenium and glutathione,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed November 13, 2019, http://riquim.fq.edu.uy/items/show/1540.
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