恶性疟原虫磷酸乙醇胺甲基转移酶与阿莫地喹复合物的晶体结构
Crystal structure of phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with amodiaquine.
机构信息
Department of Biology, Washington University, St. Louis, MO 63130, USA.
出版信息
Bioorg Med Chem Lett. 2012 Aug 1;22(15):4990-3. doi: 10.1016/j.bmcl.2012.06.032. Epub 2012 Jun 17.
Abstract
Phosphoethanolamine N-methyltransferase (PMT) is essential for phospholipid biogenesis in the malarial parasite Plasmodium falciparum. PfPMT catalyzes the triple methylation of phosphoethanolamine to produce phosphocholine, which is then used for phosphatidylcholine synthesis. Here we describe the 2.0Å resolution X-ray crystal structure of PfPMT in complex with amodiaquine. To better characterize inhibition of PfPMT by amodiaquine, we determined the IC(50) values of a series of aminoquinolines using a direct radiochemical assay. Both structural and functional analyses provide a possible approach for the development of new small molecule inhibitors of PfPMT.
摘要
磷酸乙醇胺 N-甲基转移酶（PMT）是疟原虫 Plasmodium falciparum 中磷脂生物合成所必需的。PfPMT 催化磷酸乙醇胺的三重甲基化生成磷酸胆碱，然后用于磷脂酰胆碱的合成。在这里，我们描述了 PfPMT 与阿莫地喹复合物的 2.0Å 分辨率 X 射线晶体结构。为了更好地描述阿莫地喹对 PfPMT 的抑制作用，我们使用直接放射性化学测定法测定了一系列氨基喹啉的 IC50 值。结构和功能分析为开发 PfPMT 的新型小分子抑制剂提供了一种可能的方法。
相似文献
1
Crystal structure of phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with amodiaquine.恶性疟原虫磷酸乙醇胺甲基转移酶与阿莫地喹复合物的晶体结构
Bioorg Med Chem Lett. 2012 Aug 1;22(15):4990-3. doi: 10.1016/j.bmcl.2012.06.032. Epub 2012 Jun 17.
2
Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay.利用酶偶联的转甲基化测定法鉴定恶性疟原虫磷酸乙醇胺甲基转移酶的抑制剂。
BMC Biochem. 2010 Jan 19;11:4. doi: 10.1186/1471-2091-11-4.
3
Structure and reaction mechanism of phosphoethanolamine methyltransferase from the malaria parasite Plasmodium falciparum: an antiparasitic drug target.磷酸乙醇胺甲基转移酶的结构与反应机制来自疟原虫恶性疟原虫：一种抗寄生虫药物靶标。
J Biol Chem. 2012 Jan 6;287(2):1426-34. doi: 10.1074/jbc.M111.315267. Epub 2011 Nov 23.
4
Structure, function and inhibition of the phosphoethanolamine methyltransferases of the human malaria parasites Plasmodium vivax and Plasmodium knowlesi.间日疟原虫和诺氏疟原虫这两种人类疟原虫的磷酸乙醇胺甲基转移酶的结构、功能及抑制作用
Sci Rep. 2015 Mar 12;5:9064. doi: 10.1038/srep09064.
5
Computational and experimental elucidation of Plasmodium falciparum phosphoethanolamine methyltransferase inhibitors: Pivotal drug target.计算与实验阐明恶性疟原虫磷酸乙醇胺甲基转移酶抑制剂：关键药物靶标。
PLoS One. 2019 Aug 22;14(8):e0221032. doi: 10.1371/journal.pone.0221032. eCollection 2019.
6
(1)H, (13)C, and (15)N chemical shift assignments for PfPMT, a phosphoethanolamine methyltransferase from Plasmodium falciparum.恶性疟原虫磷酸乙醇胺甲基转移酶PfPMT的（1）H、（13）C和（15）N化学位移归属
Biomol NMR Assign. 2013 Apr;7(1):17-20. doi: 10.1007/s12104-012-9372-3. Epub 2012 Mar 6.
7
An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase.恶性疟原虫磷酸乙醇胺甲基转移酶催化磷酸乙醇胺甲基化的另一种机制。
J Biol Chem. 2014 Dec 5;289(49):33815-25. doi: 10.1074/jbc.M114.611319. Epub 2014 Oct 6.
8
Biochemical and genetic analysis of the phosphoethanolamine methyltransferase of the human malaria parasite Plasmodium falciparum.人类疟原虫恶性疟原虫磷酸乙醇胺甲基转移酶的生化与遗传分析。
J Biol Chem. 2008 Mar 21;283(12):7894-900. doi: 10.1074/jbc.M709869200. Epub 2008 Jan 4.
9
A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.恶性疟原虫中一条涉及磷酸乙醇胺甲基化的磷脂酰胆碱生物合成途径。
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6206-11. doi: 10.1073/pnas.0307742101. Epub 2004 Apr 8.
10
In vivo evidence for the specificity of Plasmodium falciparum phosphoethanolamine methyltransferase and its coupling to the Kennedy pathway.恶性疟原虫磷酸乙醇胺甲基转移酶的特异性及其与肯尼迪途径偶联的体内证据。
J Biol Chem. 2005 Apr 1;280(13):12461-6. doi: 10.1074/jbc.M414626200. Epub 2005 Jan 21.
引用本文的文献
1
Antimalarial Properties of Isoquinoline Derivative from subsp. Hygroscopicus: An In Silico Approach.从 Hygroscopicus 的亚种中提取的异喹啉衍生物的抗疟特性：一种计算机模拟方法。
Biomed Res Int. 2020 Jan 9;2020:6135696. doi: 10.1155/2020/6135696. eCollection 2020.
2
Phosphoethanolamine-N-methyltransferase is a potential biomarker for the diagnosis of P. knowlesi and P. falciparum malaria.磷酸乙醇胺-N-甲基转移酶是诊断间日疟原虫和恶性疟原虫疟疾的潜在生物标志物。
PLoS One. 2018 Mar 5;13(3):e0193833. doi: 10.1371/journal.pone.0193833. eCollection 2018.
3
Conformational changes in the di-domain structure of phosphoethanolamine methyltransferase leads to active-site formation.磷酸乙醇胺甲基转移酶的双域结构构象变化导致活性位点的形成。
J Biol Chem. 2017 Dec 29;292(52):21690-21702. doi: 10.1074/jbc.RA117.000106. Epub 2017 Oct 30.
4
In vitro anthelmintic efficacy of inhibitors of phosphoethanolamine Methyltransferases in Haemonchus contortus.磷酸乙醇胺甲基转移酶抑制剂对捻转血矛线虫的体外驱虫效果
Int J Parasitol Drugs Drug Resist. 2016 Jan 18;6(1):44-53. doi: 10.1016/j.ijpddr.2016.01.002. eCollection 2016 Apr.
5
Structure, function and inhibition of the phosphoethanolamine methyltransferases of the human malaria parasites Plasmodium vivax and Plasmodium knowlesi.间日疟原虫和诺氏疟原虫这两种人类疟原虫的磷酸乙醇胺甲基转移酶的结构、功能及抑制作用
Sci Rep. 2015 Mar 12;5:9064. doi: 10.1038/srep09064.
6
An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase.恶性疟原虫磷酸乙醇胺甲基转移酶催化磷酸乙醇胺甲基化的另一种机制。
J Biol Chem. 2014 Dec 5;289(49):33815-25. doi: 10.1074/jbc.M114.611319. Epub 2014 Oct 6.
7
Nematode phospholipid metabolism: an example of closing the genome-structure-function circle.线虫类的磷脂代谢：一个封闭基因组-结构-功能循环的范例。
Trends Parasitol. 2014 May;30(5):241-50. doi: 10.1016/j.pt.2014.03.001. Epub 2014 Mar 28.
8
Amodiaquine, an antimalarial drug, inhibits dengue virus type 2 replication and infectivity.阿莫地喹是一种抗疟药物，可抑制2型登革热病毒的复制和传染性。
Antiviral Res. 2014 Jun;106:125-34. doi: 10.1016/j.antiviral.2014.03.014. Epub 2014 Mar 27.
9
Evolution of structure and mechanistic divergence in di-domain methyltransferases from nematode phosphocholine biosynthesis.线虫磷酸胆碱生物合成中二域甲基转移酶的结构演变和机制分化。
Structure. 2013 Oct 8;21(10):1778-87. doi: 10.1016/j.str.2013.07.023. Epub 2013 Sep 5.
本文引用的文献
1
Structure and reaction mechanism of phosphoethanolamine methyltransferase from the malaria parasite Plasmodium falciparum: an antiparasitic drug target.磷酸乙醇胺甲基转移酶的结构与反应机制来自疟原虫恶性疟原虫：一种抗寄生虫药物靶标。
J Biol Chem. 2012 Jan 6;287(2):1426-34. doi: 10.1074/jbc.M111.315267. Epub 2011 Nov 23.
2
Thermodynamic evaluation of ligand binding in the plant-like phosphoethanolamine methyltransferases of the parasitic nematode Haemonchus contortus.植物样磷酸乙醇胺甲基转移酶的寄生性线虫旋毛虫的配体结合热力学评价。
J Biol Chem. 2011 Nov 4;286(44):38060-38068. doi: 10.1074/jbc.M111.290619. Epub 2011 Sep 13.
3
Phosphoethanolamine methyltransferases in phosphocholine biosynthesis: functions and potential for antiparasite therapy.磷酸乙醇胺甲基转移酶在磷酸胆碱生物合成中的作用及其在抗寄生虫治疗中的潜力。
FEMS Microbiol Rev. 2011 Jul;35(4):609-19. doi: 10.1111/j.1574-6976.2011.00267.x. Epub 2011 Mar 10.
4
PHENIX: a comprehensive Python-based system for macromolecular structure solution.PHENIX：一个基于Python的用于大分子结构解析的综合系统。
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. doi: 10.1107/S0907444909052925. Epub 2010 Jan 22.
5
Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay.利用酶偶联的转甲基化测定法鉴定恶性疟原虫磷酸乙醇胺甲基转移酶的抑制剂。
BMC Biochem. 2010 Jan 19;11:4. doi: 10.1186/1471-2091-11-4.
6
Artemisinin resistance in Plasmodium falciparum malaria.恶性疟原虫疟疾中的青蒿素耐药性。
N Engl J Med. 2009 Jul 30;361(5):455-67. doi: 10.1056/NEJMoa0808859.
7
Phaser crystallographic software.相位结晶学软件。
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674. doi: 10.1107/S0021889807021206. Epub 2007 Jul 13.
8
Disruption of the Plasmodium falciparum PfPMT gene results in a complete loss of phosphatidylcholine biosynthesis via the serine-decarboxylase-phosphoethanolamine-methyltransferase pathway and severe growth and survival defects.恶性疟原虫PfPMT基因的破坏导致通过丝氨酸脱羧酶-磷酸乙醇胺甲基转移酶途径的磷脂酰胆碱生物合成完全丧失，并出现严重的生长和存活缺陷。
J Biol Chem. 2008 Oct 10;283(41):27636-27643. doi: 10.1074/jbc.M804360200. Epub 2008 Aug 11.
9
Biochemical and genetic analysis of the phosphoethanolamine methyltransferase of the human malaria parasite Plasmodium falciparum.人类疟原虫恶性疟原虫磷酸乙醇胺甲基转移酶的生化与遗传分析。
J Biol Chem. 2008 Mar 21;283(12):7894-900. doi: 10.1074/jbc.M709869200. Epub 2008 Jan 4.
10
Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies.通过常规监测应对抗疟药物耐药性挑战，以更新国家疟疾治疗政策。
Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):153-9.
Zotero 插件