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

Ewelina Guca, Gergely N. Nagy, Fanni Hajdú, Lívia Marton, Richard Izrael, François Hoh, Yinshan Yang, Henri Vial, B. Vértessy, Jean François Guichou, Rachel Cerdan

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number11215
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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Choline-Phosphate Cytidylyltransferase
Plasmodium
Antimalarials
Phosphatidylcholines
Malaria
Lysine
Catalytic Domain
Phospholipids
Ligands
Lipids
Membranes
Falciparum Malaria
Drug Design
Enzymes
Threonine
Parasites
Erythrocytes

ASJC Scopus subject areas

  • General

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Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis. / Guca, Ewelina; Nagy, Gergely N.; Hajdú, Fanni; Marton, Lívia; Izrael, Richard; Hoh, François; Yang, Yinshan; Vial, Henri; Vértessy, B.; Guichou, Jean François; Cerdan, Rachel.

In: Scientific Reports, Vol. 8, No. 1, 11215, 01.12.2018.

Research output: Contribution to journalArticle

Guca, E, Nagy, GN, Hajdú, F, Marton, L, Izrael, R, Hoh, F, Yang, Y, Vial, H, Vértessy, B, Guichou, JF & Cerdan, R 2018, 'Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis', Scientific Reports, vol. 8, no. 1, 11215. https://doi.org/10.1038/s41598-018-29500-9
Guca, Ewelina ; Nagy, Gergely N. ; Hajdú, Fanni ; Marton, Lívia ; Izrael, Richard ; Hoh, François ; Yang, Yinshan ; Vial, Henri ; Vértessy, B. ; Guichou, Jean François ; Cerdan, Rachel. / Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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