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Plasmodium falciparum CTP:phosphocholine cytidylyltransferase possesses two functional catalytic domains and is inhibited by a CDP‐choline analog selected from a virtual screening
Author(s) -
Contet Alicia,
Pihan Emilie,
Lavigne Marina,
Wengelnik Kai,
Maheshwari Sweta,
Vial Henri,
Douguet Dominique,
Cerdan Rachel
Publication year - 2015
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2015.03.003
Subject(s) - phosphocholine , plasmodium falciparum , choline , chemistry , biochemistry , biology , immunology , malaria , phospholipid , phosphatidylcholine , membrane
Phosphatidylcholine is the major lipid component of the malaria parasite membranes and is required for parasite multiplication in human erythrocytes. Plasmodium falciparum CTP:phosphocholine cytidylyltransferase ( Pf CCT) is the rate‐limiting enzyme of the phosphatidylcholine biosynthesis pathway and thus considered as a potential antimalarial target. In contrast to its mammalian orthologs, Pf CCT contains a duplicated catalytic domain. Here, we show that both domains are catalytically active with similar kinetic parameters. A virtual screening strategy allowed the identification of a drug‐size molecule competitively inhibiting the enzyme. This compound also prevented phosphatidylcholine biosynthesis in parasites and exerted an antimalarial effect. This study constitutes the first step towards a rationalized design of future new antimalarial agents targeting Pf CCT.