Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis
| العنوان: | Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis |
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| المؤلفون: | Gergely N. Nagy, Rachel Cerdan, Yinshan Yang, François Hoh, Jean-François Guichou, Henri Vial, Fanni Hajdú, Beáta G. Vértessy, Ewelina Guca, Lívia Marton, Richard Izrael |
| المساهمون: | Department of Biochemistry and Molecular Biology [Debrecen, Hungary], University of Debrecen [Hungary], Ningxia Medical College, Dynamique moléculaire des interactions membranaires (DMIM), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) Scientific Reports 'Scientific Reports ', vol: 8, pages: 11215-1-11215-13 (2018) Scientific Reports, Nature Publishing Group, 2018, 8 (1), ⟨10.1038/s41598-018-29500-9⟩ |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Plasmodium falciparum, Cytidylyltransferase, lcsh:Medicine, Ligands, Catalysis, Article, Substrate Specificity, Antimalarials, 03 medical and health sciences, chemistry.chemical_compound, Biosynthesis, Catalytic Domain, Lipid biosynthesis, parasitic diseases, Animals, Humans, Amino Acid Sequence, Choline-Phosphate Cytidylyltransferase, Malaria, Falciparum, Threonine, lcsh:Science, Phosphocholine, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Lipogenesis, lcsh:R, Active site, biology.organism_classification, Lipids, 3. Good health, Kinetics, 030104 developmental biology, Biochemistry, chemistry, Membrane biogenesis, biology.protein, lcsh:Q, Protein Binding |
| الوصف: | The development of the malaria parasite, Plasmodium falciparum, in the human erythrocyte, relies on phospholipid metabolism to fulfil the massive need for membrane biogenesis. Phosphatidylcholine (PC) is the most abundant phospholipid in Plasmodium membranes. PC biosynthesis is mainly ensured by the de novo Kennedy pathway that is considered as an antimalarial drug target. The CTP:phosphocholine cytidylyltransferase (CCT) catalyses the rate-limiting step of the Kennedy pathway. Here we report a series of structural snapshots of the PfCCT catalytic domain in its free, substrate- and product-complexed states that demonstrate the conformational changes during the catalytic mechanism. Structural data show the ligand-dependent conformational variations of a flexible lysine. Combined kinetic and ligand-binding analyses confirm the catalytic roles of this lysine and of two threonine residues of the helix αE. Finally, we assessed the variations in active site residues between Plasmodium and mammalian CCT which could be exploited for future antimalarial drug design. |
| وصف الملف: | application/pdf |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3ec05d8dbd2d41ca90041adffa6d92a https://doi.org/10.1038/s41598-018-29500-9 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c3ec05d8dbd2d41ca90041adffa6d92a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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