title: Structure of the (E)-4-hydroxy-3-methyl-but-2-enyl-diphosphate reductase from Plasmodium falciparum.
abstract: Terpenoid precursor biosynthesis occurs in human and many pathogenic organisms via the mevalonate and 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways, respectively. We determined the X-ray structure of the Fe/S containing (E)-4-hydroxy-3-methyl-but-2-enyl-diphosphate reductase (LytB) of the pathogenic protozoa Plasmodium falciparum which catalyzes the terminal step of the MEP pathway. The cloverleaf fold and the active site of P. falciparum LytB corresponds to those of the Aquifex aeolicus and Escherichia coli enzymes. Its distinct electron donor [2Fe-2S] ferredoxin was modeled to its binding site by docking calculations. The presented structural data provide a platform for a rational search of anti-malarian drugs.
authors.affiliation: Medizinische Klinik IV (Hämatologie), Justus-Liebig-Universität Giessen, Klinikstrasse 33, D-35392 Giessen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Rekittke
authors.forename: Elena
authors.initials: E
authors.lastname: Olkhova
authors.forename: Jochen
authors.initials: J
authors.lastname: Wiesner
authors.forename: Ulrike
authors.initials: U
authors.lastname: Demmer
authors.forename: Eberhard
authors.initials: E
authors.lastname: Warkentin
authors.forename: Hassan
authors.initials: H
authors.lastname: Jomaa
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ermler
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D005288:Ferredoxins / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009943:Organophosphorus Compounds / Q000378:metabolism*; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C547602:(E)-4-hydroxy-3-methylbut-2-enyl diphosphate; D005288:Ferredoxins; D009943:Organophosphorus Compounds; D015800:Protozoan Proteins; D010088:Oxidoreductases
keywords: (E)-4-hydroxy-3-methyl-but-2-enyl-diphosphate; (E)-4-hydroxy-3-methyl-but-2-enyl-diphosphate reductase; 2-C-methyl-d-erythritol-2,4-cyclo-diphosphate; 2-C-methyl-d-erythritol-4-phosphate; DMAPP; Drug design; HMBPP; IPP; Isoprenoid biosynthesis; LytB; MEP; MEcPP; Plasmodium falciparum; X-ray structure; dimethylallyl diphosphate; isopentenyl diphosphate