Structure, function and inhibition of the phosphoethanolamine methyltransferases of the human malaria parasites Plasmodium vivax and Plasmodium knowlesi.
Structure, function and inhibition of the phosphoethanolamine methyltransferases of the human malaria parasites Plasmodium vivax and Plasmodium knowlesi.
复制标题
人类疟原虫疟原虫的磷酸乙醇胺甲基转移酶的结构，功能和抑制作用。
DOI：
10.1038/srep09064
复制
发表时间：
2015-03-12
影响因子：
4.6
通讯作者：
Ben Mamoun C
中科院分区：
文献类型：
--
作者：
Garg A;Lukk T;Kumar V;Choi JY;Augagneur Y;Voelker DR;Nair S;Ben Mamoun C
磷酸乙醇胺甲基转移酶（PMT）催化磷酸乙醇胺的三步甲基化以形成磷酸胆碱，这是包括人类疟疾寄生虫、线虫和植物在内的选定数量的真核生物中合成磷脂酰胆碱的关键步骤。恶性疟原虫的遗传研究表明甲基转移酶PfPMT在疟原虫发育和分化中起着关键作用。PMT直系同源物在感染人类的其他疟疾寄生虫中的存在以及它们在哺乳动物中的缺失使它们成为开发对不同疟原虫物种具有广泛特异性的选择性抗疟药的理想靶标。在这里，我们描述的X-射线结构和生化特性的PMT直向同源物从间日疟原虫和诺氏疟原虫，并表明这两种酶被抑制阿莫地喹和NSC 158011，两种药物具有强效抗疟活性。在依赖PkPMT或PvPMT存活的酵母突变体中的代谢研究表明，这些化合物抑制乙醇胺的磷脂酰胆碱生物合成。我们的结构和功能数据为PMT酶的催化和抑制机制提供了见解，并为更好地设计更具特异性和选择性的抗疟药物奠定了基础。
Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.
登录
查看更多内容
影响因子：
--
作者：
Bobenchik, April M.;Choi, Jae-Yeon;Ben Mamoun, Choukri
通讯作者：
Ben Mamoun, Choukri
影响因子：
4.8
作者：
Choi, Jae-Yeon;Augagneur, Yoann;Voelker, Dennis R.
通讯作者：
Voelker, Dennis R.
影响因子：
64.8
作者：
Carlton, Jane M.;Adams, John H.;Silva, Joana C.;Bidwell, Shelby L.;Lorenzi, Hernan;Caler, Elisabet;Crabtree, Jonathan;Angiuoli, Samuel V.;Merino, Emilio F.;Amedeo, Paolo;Cheng, Qin;Coulson, Richard M. R.;Crabb, Brendan S.;del Portillo, Hernando A.;Essien, Kobby;Feldblyum, Tamara V.;Fernandez-Becerra, Carmen;Gilson, Paul R.;Gueye, Amy H.;Guo, Xiang;Kang'a, Simon;Kooij, Taco W. A.;Korsinczky, Michael;Meyer, Esmeralda V. -S.;Nene, Vish;Paulsen, Ian;White, Owen;Ralph, Stuart A.;Ren, Qinghu;Sargeant, Tobias J.;Salzberg, Steven L.;Stoeckert, Christian J.;Sullivan, Steven A.;Yamamoto, Marcio M.;Hoffman, Stephen L.;Wortman, Jennifer R.;Gardner, Malcolm J.;Galinski, Mary R.;Barnwell, John W.;Fraser-Liggett, Claire M.
通讯作者：
Fraser-Liggett, Claire M.
影响因子：
2.7
作者：
Lee, Soon Goo;Alpert, Tara D.;Jez, Joseph M.
通讯作者：
Jez, Joseph M.
影响因子：
4.1
作者：
Brendza, Katherine M.;Haakenson, William;Jez, Joseph M.
通讯作者：
Jez, Joseph M.