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J. Biol. Chem., Vol. 283, Issue 24, 16342-16354, June 13, 2008

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Glucose-induced Remodeling of Intermediary and Energy Metabolism in Procyclic Trypanosoma brucei^*

Virginie Coustou, Marc Biran, Marc Breton, Fabien Guegan, Loïc Rivière, Nicolas Plazolles, Derek Nolan^¶, Michael P. Barrett^||, Jean-Michel Franconi, and Frédéric Bringaud¹

From the Laboratoire de Microbiologie Cellulaire et Moléculaire et Pathogénicité, UMR-5234 CNRS, and the Centre de Résonance Magnétique des Systèmes Biologiques, UMR-5536 CNRS, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France, the ^¶School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland, and the ^||Institute of Biomedical and Life Sciences, Division of Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, Scotland, United Kingdom

The procyclic form of Trypanosoma brucei is a parasitic protozoan that normally dwells in the midgut of its insect vector. In vitro, this parasite prefers D-glucose to L -proline as a carbon source, although this amino acid is the main carbon source available in its natural habitat. Here, we investigated how L -proline is metabolized in glucose-rich and glucose-depleted conditions. Analysis of the excreted end products of ¹³C-enriched L -proline metabolism showed that the amino acid is converted into succinate or L -alanine depending on the presence or absence of D-glucose, respectively. The fact that the pathway of L -proline metabolism was truncated in glucose-rich conditions was confirmed by the analysis of 13 separate RNA interference-harboring or knock-out cell lines affecting different steps of this pathway. For instance, RNA interference studies revealed the loss of succinate dehydrogenase activity to be conditionally lethal only in the absence of D-glucose, confirming that in glucose-depleted conditions, L -proline needs to be converted beyond succinate. In addition, depletion of the F₀/F₁-ATP synthase activity by RNA interference led to cell death in glucose-depleted medium, but not in glucose-rich medium. This implies that, in the presence of D-glucose, the importance of the F₀/F₁-ATP synthase is diminished and ATP is produced by substrate level phosphorylation. We conclude that trypanosomes develop an elaborate adaptation of their energy production pathways in response to carbon source availability.

Received for publication, November 26, 2007 , and in revised form, April 9, 2008.

^* This work was supported by CNRS, the Université Victor Segalen Bordeaux 2, and the Ministère des Affaires Etrangères et Européennes (Programme Alliance). 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Centre de Résonance Magnétique des Systèmes Biologiques, UMR-5536 CNRS, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France. Tel.: 33-5-5757-4632; Fax: 33-5-5757-4556; E-mail: bringaud{at}rmsb.u-bordeaux2.fr.

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