Plasmodium falciparum CTP:phosphocholine cytidylyltransferase possesses two functional catalytic domains and is inhibited by a CDP-choline analog selected from a virtual screening

被引：11

作者：

Contet, Alicia ^{[1
]}

Pihan, Emilie ^{[2
]}

Lavigne, Marina ^{[1
]}

Wengelnik, Kai ^{[1
]}

Maheshwari, Sweta ^{[1
]}

Vial, Henri ^{[1
]}

Douguet, Dominique ^{[2
]}

Cerdan, Rachel ^{[1
]}

机构：

[1] Univ Montpellier, CNRS, Dynam Interact Membranaires Normales & Pathol, UMR 5235, F-34095 Montpellier, France

[2] Univ Nice Sophia Antipolis, CNRS, Inst Pharmacol Mol & Cell, UMR 7275, F-06560 Valbonne, France

来源：

FEBS LETTERS | 2015年 / 589卷 / 09期

关键词：

Malaria; Phosphatidylcholine; CTP:phosphocholine cytidylyltransferase (EC 2.7.7.15); Kinetic parameter; Drug target; Structure-based virtual screening; Inhibitor; CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; PHOSPHOETHANOLAMINE METHYLTRANSFERASE; AMPHIPATHIC HELIX; STRUCTURAL BASIS; MALARIA; BIOSYNTHESIS; ALIGNMENT; PATHWAY; ENZYME; SALTS;

D O I：

10.1016/j.febslet.2015.03.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (PfCCT) is the rate-limiting enzyme of the phosphatidylcholine biosynthesis pathway and thus considered as a potential antimalarial target. In contrast to its mammalian orthologs, PfCCT 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 PfCCT. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

引用

页码：992 / 1000

页数：9

共 32 条

[1] In vivo antimalarial activities of mono- and bis quaternary ammonium salts interfering with Plasmodium phospholipid metabolism [J].