Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Türbachova I, Eberl M, Zeidler J, Lichtenthaler H K, Soldati D, Beck E
Institute of Biochemistry, Academic Hospital Centre, Justus-Liebig-University, Friedrichstrasse 24, D-35392 Giessen, Germany.
Science. 1999 Sep 3;285(5433):1573-6. doi: 10.1126/science.285.5433.1573.
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.
恶性疟原虫中存在的一条不依赖甲羟戊酸的类异戊二烯生物合成途径被证明是疟疾化疗的有效靶点。该途径包括1-脱氧-D-木酮糖5-磷酸（DOXP）作为关键代谢物。编码DOXP合酶和DOXP还原异构酶的两个基因的存在表明恶性疟原虫中的类异戊二烯生物合成依赖于DOXP途径。该途径可能位于顶质体中。重组恶性疟原虫DOXP还原异构酶受到磷霉素及其衍生物FR-900098的抑制。这两种药物都抑制了多药耐药恶性疟原虫菌株的体外生长。用这些药物治疗后，感染啮齿类疟原虫文氏疟原虫的小鼠被治愈。
