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

Ewelina Guca , Gergely Nagy (1) , Fanni Hajdú , Lívia Marton , Richard Izrael , François Hoh (2) , Yinshan Yang (3) , Henri Vial (4) , Beata Vértessy , Jean-François Guichou (2) , Rachel Cerdan (5)

1 Department of Biochemistry and Molecular Biology [Debrecen, Hungary]
2 CBS - Centre de Biochimie Structurale [Montpellier]
3 Ningxia Medical College
4 DMIM - Dynamique moléculaire des interactions membranaires
5 DIMNP - Dynamique des interactions membranaires normales et pathologiques

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 productcomplexed 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.

Domaines: Biologie structurale [q-bio.BM]

Ewelina Guca, Gergely Nagy, Fanni Hajdú, Lívia Marton, Richard Izrael, et al.. Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis. Scientific Reports, 2018, 8 (1), ⟨10.1038/s41598-018-29500-9⟩. ⟨hal-02359357⟩