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J. Biol. Chem., Vol. 279, Issue 50, 51749-51759, December 10, 2004

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The Methylerythritol Phosphate Pathway Is Functionally Active in All Intraerythrocytic Stages of Plasmodium falciparum^*

María B. Cassera, Fabio C. Gozzo¶, Fabio L. D'Alexandri, Emilio F. Merino, Hernando A. del Portillo||, Valnice J. Peres, Igor C. Almeida||, Marcos N. Eberlin¶, Gerhard Wunderlich, Jochen Wiesner**, Hassan Jomaa**, Emilia A. Kimura, and Alejandro M. Katzin||

From the Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, Brazil, the ^¶Thomson Mass Spectrometry Laboratory, Institute of Chemistry, State University of Campinas, 13083-970 Campinas, Brazil, and the ^**Institute of Biochemistry, Justus-Liebig-University, D-35392, Giessen, Germany

Two genes encoding the enzymes 1-deoxy-D-xylulose-5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase have been recently identified, suggesting that isoprenoid biosynthesis in Plasmodium falciparum depends on the methylerythritol phosphate (MEP) pathway, and that fosmidomycin could inhibit the activity of 1-deoxy-D-xylulose-5-phosphate reductoisomerase. The metabolite 1-deoxy-D-xylulose-5-phosphate is not only an intermediate of the MEP pathway for the biosynthesis of isopentenyl diphosphate but is also involved in the biosynthesis of thiamin (vitamin B₁) and pyridoxal (vitamin B₆) in plants and many microorganisms. Herein we report the first isolation and characterization of most downstream intermediates of the MEP pathway in the three intraerythrocytic stages of P. falciparum. These include, 1-deoxy-D-xylulose-5-phosphate, 2-C-methyl-D-erythritol-4-phosphate, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol-2-phosphate, and 2-C-methyl-D-erythritol-2,4-cyclodiphosphate. These intermediates were purified by HPLC and structurally characterized via biochemical and electrospray mass spectrometric analyses. We have also investigated the effect of fosmidomycin on the biosynthesis of each intermediate of this pathway and isoprenoid biosynthesis (dolichols and ubiquinones). For the first time, therefore, it is demonstrated that the MEP pathway is functionally active in all intraerythrocytic forms of P. falciparum, and de novo biosynthesis of pyridoxal in a protozoan is reported. Its absence in the human host makes both pathways very attractive as potential new targets for antimalarial drug development.

Received for publication, July 23, 2004 , and in revised form, September 22, 2004.

^* This work was supported in part by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, PRONEX, and UNDP/World Bank/WHO-TDR, European Commission INCO-Dev, 5th Framework Programme Contract ICA4-CT-2001-10078. 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 Figs. Data I and II.

Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo.

^|| Research fellows from Conselho Nacional de Desenvolvimento Científico e Tecnológico.

To whom correspondence should be addressed: Laboratory of Malaria, Dept. of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Lineu Prestes 1374, 05508-900, São Paulo, SP, Brazil. Tel.: 55-11-3091-7330; Fax: 55-11-3091-7417; E-mail: amkatzin{at}icb.usp.br.

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