Crystal structure of the inhibitor-free form of 1-deoxy-D-xylulose 5-phosphate reductoisomerase from Plasmodium falciparum

Introduction Malaria is one of the world’s most serious parasitic diseases. There are estimated 300-500 million cases and more than a million deaths from malaria each year. Human malaria is caused by infection with intracellular parasites of the genus Plasmodium that are transmitted by Anopheles mosquitoes. Plasmodium falciparum is the most lethal among the four species of Plasmodium that infect humans. The emergence of strains of malarial parasite resistant to conventional drug therapy, such as chloroquine, amodiaquine, and sulfadoxinepyrimethamine, has stimulated searches for antimalarials with novel modes of action. The non-mevalonate pathway of isoprenoid biosynthesis present in Plasmodium falciparum is known to be an effective target of antimalarial drugs. The second enzyme of the non-mevalonate pathway, 1-deoxy-Dxylulose 5-phosphate reductoisomerase (DXR, EC 1.1.1.267), catalyzes the NADPH and divalent cation (Mg or Mn)-dependent transformation of 1-deoxy-Dxylulose 5-phosphate into 2-C-mthyl-D-erythritol 4phosphate. To date several crystal structures of DXR from Escherichia coli, Zymomonas mobilis, Mycobacterium tuberculosis, and Thermotoga maritima have been reported. However, the crystal structure of Plasmodium falciparum DXR (PfDXR) itself has not yet been reported. Here we report the crystal structure of recombinant PfDXR.