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Science 3 September 1999:
Vol. 285. no. 5433, pp. 1573 - 1576
DOI: 10.1126/science.285.5433.1573
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Reports

Inhibitors of the Nonmevalonate Pathway of Isoprenoid Biosynthesis as Antimalarial Drugs

Hassan Jomaa, 1* Jochen Wiesner, 1 Silke Sanderbrand, 1 Boran Altincicek, 1 Claus Weidemeyer, 1 Martin Hintz, 1 Ivana Türbachova, 2 Matthias Eberl, 1 Johannes Zeidler, 3 Hartmut K. Lichtenthaler, 3 Dominique Soldati, 2 Ewald Beck 1

A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably located in the apicoplast. The recombinant P. falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its derivative, FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.

1 Institute of Biochemistry, Academic Hospital Centre, Justus-Liebig-University, Friedrichstrasse 24, D-35392 Giessen, Germany.
2 Zentrum für Molekulare Biologie, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany.
3 Botanisches Institut II, University of Karlsruhe, Kaiserstrasse 12, D-76128 Karlsruhe, Germany.
*   To whom correspondence should be addressed. E-mail: hassan.jomaa{at}biochemie.med.uni-giessen.de

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H. Luttgen, F. Rohdich, S. Herz, J. Wungsintaweekul, S. Hecht, C. A. Schuhr, M. Fellermeier, S. Sagner, M. H. Zenk, A. Bacher, et al. (2000)
PNAS 97, 1062-1067
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Analysis of targeting sequences demonstrates that trafficking to the Toxoplasma gondii plastid branches off the secretory system.
A DeRocher, C. Hagen, J. Froehlich, J. Feagin, and M Parsons (2000)
J. Cell Sci. 113, 3969-3977
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Isopentenyl diphosphate biosynthesis via a mevalonate-independent pathway: Isopentenyl monophosphate kinase catalyzes the terminal enzymatic step.
B. M. Lange and R. Croteau (1999)
PNAS 96, 13714-13719
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Growth of Toxoplasma gondii is inhibited by aryloxyphenoxypropionate herbicides targeting acetyl-CoA carboxylase.
E. Zuther, J. J. Johnson, R. Haselkorn, R. McLeod, and P. Gornicki (1999)
PNAS 96, 13387-13392
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Structure and Mechanism of 2-C-Methyl-D-erythritol 2,4-Cyclodiphosphate Synthase. AN ENZYME IN THE MEVALONATE-INDEPENDENT ISOPRENOID BIOSYNTHETIC PATHWAY.
S. B. Richard, J.-L. Ferrer, M. E. Bowman, A. M. Lillo, C. N. Tetzlaff, D. E. Cane, and J. P. Noel (2002)
J. Biol. Chem. 277, 8667-8672
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Characterization of 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase, an Enzyme Involved in Isopentenyl Diphosphate Biosynthesis, and Identification of Its Catalytic Amino Acid Residues.
T. Kuzuyama, S. Takahashi, M. Takagi, and H. Seto (2000)
J. Biol. Chem. 275, 19928-19932
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Apicomplexan Parasites Possess Distinct Nuclear-encoded, but Apicoplast-localized, Plant-type Ferredoxin-NADP+ Reductase and Ferredoxin.
M. Vollmer, N. Thomsen, S. Wiek, and F. Seeber (2001)
J. Biol. Chem. 276, 5483-5490
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1-Deoxy-D-xylulose-5-phosphate Synthase, a Limiting Enzyme for Plastidic Isoprenoid Biosynthesis in Plants.
J. M. Estevez, A. Cantero, A. Reindl, S. Reichler, and P. Leon (2001)
J. Biol. Chem. 276, 22901-22909
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Targeting and Processing of Nuclear-encoded Apicoplast Proteins in Plastid Segregation Mutants of Toxoplasma gondii.
C. Y. He, B. Striepen, C. H. Pletcher, J. M. Murray, and D. S. Roos (2001)
J. Biol. Chem. 276, 28436-28442
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Studies on the nonmevalonate terpene biosynthetic pathway: Metabolic role of IspH (LytB) protein.
F. Rohdich, S. Hecht, K. Gartner, P. Adam, C. Krieger, S. Amslinger, D. Arigoni, A. Bacher, and W. Eisenreich (2002)
PNAS 99, 1158-1163
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Biosynthesis of terpenoids: YgbB protein converts 4-diphosphocytidyl-2C-methyl-D-erythritol 2-phosphate to 2C-methyl-D-erythritol 2,4-cyclodiphosphate.
S. Herz, J. Wungsintaweekul, C. A. Schuhr, S. Hecht, H. Luttgen, S. Sagner, M. Fellermeier, W. Eisenreich, M. H. Zenk, A. Bacher, et al. (2000)
PNAS 97, 2486-2490
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Subcellular localization of acetyl-CoA carboxylase in the apicomplexan parasite Toxoplasma gondii.
J. Jelenska, M. J. Crawford, O. S. Harb, E. Zuther, R. Haselkorn, D. S. Roos, and P. Gornicki (2001)
PNAS 98, 2723-2728
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Biosynthesis of terpenoids: 4-Diphosphocytidyl-2-C-methyl-D-erythritol kinase from tomato.
F. Rohdich, J. Wungsintaweekul, H. Luttgen, M. Fischer, W. Eisenreich, C. A. Schuhr, M. Fellermeier, N. Schramek, M. H. Zenk, and A. Bacher (2000)
PNAS 97, 8251-8256
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Lateral transfer at the gene and subgenic levels in the evolution of eukaryotic enolase.
P. J. Keeling and J. D. Palmer (2001)
PNAS 98, 10745-10750
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Isoprenoid biosynthesis: The evolution of two ancient and distinct pathways across genomes.
B. M. Lange, T. Rujan, W. Martin, and R. Croteau (2000)
PNAS 97, 13172-13177
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