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J. Biol. Chem., Vol. 279, Issue 7, 5249-5256, February 13, 2004

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The Amitochondriate Eukaryote Trichomonas vaginalis Contains a Divergent Thioredoxin-linked Peroxiredoxin Antioxidant System^*

Graham H. Coombs, Gareth D. Westrop, Pavel Suchan, Gabriela Puzova, Robert P. Hirt¶||, T. Martin Embley¶, Jeremy C. Mottram**, and Sylke Müller¶¶

From the Division of Infection & Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Joseph Black Bldg., Glasgow G12 8QQ, United Kingdom, the ^¶Department of Zoology, The Natural History Museum, Cromwell Road, London SW7 5BD, United Kingdom, the ^**Wellcome Centre for Molecular Parasitology, University of Glasgow, The Anderson College, Glasgow G11 6NU, United Kingdom, and the School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom

Trichomonas is an amitochondriate parasitic protozoon specialized for an anaerobic lifestyle. Nevertheless, it is exposed to oxygen and is able to cope with the resultant oxidative stress. In the absence of glutathione, cysteine has been thought to be the major antioxidant. We now report that the parasite contains thioredoxin reductase, which functions together with thioredoxin and thioredoxin peroxidase to detoxify potentially damaging oxidants. Thioredoxin reductase and thioredoxin also reduce cystine and so may play a role in maintaining the cellular cysteine levels. The importance of the thioredoxin system as one of the major antioxidant defense mechanisms in Trichomonas was confirmed by showing that the parasite responds to environmental changes resulting in increased oxidative stress by up-regulating thioredoxin and thioredoxin peroxidases levels. Sequence data indicate that the thioredoxin reductase of Trichomonas differs fundamentally in structure from that of its human host and thus may represent a useful drug target. The protein is generally similar to thioredoxin reductases present in other lower eukaryotes, all of which probably originated through horizontal gene transfer from a prokaryote. The phylogenetic signal in thioredoxin peroxidase is weak, but evidence from trees suggests that this gene has been subject to repeated horizontal gene transfers from different prokaryotes to different eukaryotes. The data are thus consistent with the complexity hypothesis that predicts that the evolution of simple pathways such as the thioredoxin cascade are likely to be affected by horizontal gene transfer between species.

Received for publication, April 25, 2003 , and in revised form, November 11, 2003.

^* The work was supported in part by the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ507830, AJ507831, and AJ507832.

^|| Supported by a Wellcome Trust University Award (060068).

A Medical Research Council (United Kingdom) Senior Fellow.

^¶¶ A Wellcome Trust Senior Fellow.

To whom correspondence should be addressed. Tel.: 44-141-330-4777; Fax: 44-141-330-3516; E-mail: g.coombs{at}bio.gla.ac.uk.

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