Molecular characterization of a novel geranylgeranyl pyrophosphate synthase from Plasmodium parasites
| العنوان: | Molecular characterization of a novel geranylgeranyl pyrophosphate synthase from Plasmodium parasites |
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| المؤلفون: | F. Hal Ebetino, Y. Zhao, Jocelyne Lew, Udo Oppermann, Matthieu Schapira, James E. Dunford, R. Graham G. Russell, Raymond Hui, Jennifer D. Artz, Aiping Dong, Amy K. Wernimont |
| المصدر: | The Journal of Biological Chemistry |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Protein Structure, Geranylgeranyl pyrophosphate, Stereochemistry, Nitrogen, Protein subunit, Amino Acid Motifs, Farnesyl pyrophosphate, Plasmodium Parasites, Biology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Inhibitory Concentration 50, Isoprenoid, Protein structure, Polyisoprenyl Phosphates, Structural Biology, Yeasts, Transferase, Humans, Magnesium, Asparagine, Amino Acid Sequence, Enzyme Inhibitors, Molecular Biology, 030304 developmental biology, 0303 health sciences, Diphosphonates, 030306 microbiology, Enzymes/Inhibitors, Cell Biology, Lyase, Terpenoid, 3. Good health, Malaria, chemistry, Organisms/Parasite, Amino-bisphosphonates, Geranylgeranyl-Diphosphate Geranylgeranyltransferase, Protozoan, Enzymology, Plasmodium vivax, Hydrophobic and Hydrophilic Interactions |
| الوصف: | We present here a study of a eukaryotic trans-prenylsynthase from the malaria pathogen Plasmodium vivax. Based on the results of biochemical assays and contrary to previous indications, this enzyme catalyzes the production of geranylgeranyl pyrophosphate (GGPP) rather than farnesyl pyrophosphate (FPP). Structural analysis shows that the product length is constrained by a hydrophobic cavity formed primarily by a set of residues from the same subunit as the product as well as at least one other from the dimeric partner. Furthermore, Plasmodium GGPP synthase (GGPPS) can bind nitrogen-containing bisphosphonates (N-BPs) strongly with the energetically favorable cooperation of three Mg(2+), resulting in inhibition by this class of compounds at IC(50) concentrations below 100 nM. In contrast, human and yeast GGPPSs do not accommodate a third magnesium atom in the same manner, resulting in their insusceptibility to N-BPs. This differentiation is in part attributable to a deviation in a conserved motif known as the second aspartate-rich motif: whereas the aspartates at the start and end of the five-residue motif in FFPP synthases and P. vivax GGPPSs both participate in the coordination of the third Mg(2+), an asparagine is featured as the last residue in human and yeast GGPPSs, resulting in a different manner of interaction with nitrogen-containing ligands. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e23d9558b722225da206530dffb40adb http://ora.ox.ac.uk/objects/uuid:187c8306-de20-4880-a066-2b4e0d6dd388 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e23d9558b722225da206530dffb40adb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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