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Sci Rep. 2018 Jul 25;8(1):11215. doi: 10.1038/s41598-018-29500-9.

Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis.

Author information

1
Dynamique des Interactions Membranaires Normales et Pathologiques, UMR 5235, CNRS, Université de Montpellier, Montpellier, France.
2
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Carrer de Baldiri Reixac 10, 08028, Barcelona, Spain.
3
Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Budapest, Hungary.
4
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
5
Division of Structural Biology, University of Oxford, Roosevelt Drive, Oxford, OX37BN, United Kingdom.
6
Doctoral School of Multidisciplinary Medical Science, University of Szeged, Szeged, Hungary.
7
CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, Montpellier, France.
8
INSERM U1054, Montpellier, France.
9
Dynamique des Interactions Membranaires Normales et Pathologiques, UMR 5235, CNRS, Université de Montpellier, Montpellier, France. rachel.cerdan@umontpellier.fr.

Abstract

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.

PMID:
30046154
PMCID:
PMC6060094
DOI:
10.1038/s41598-018-29500-9
[Indexed for MEDLINE]
Free PMC Article

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